EA042018B1 - NLRP3 MODULATORS - Google Patents

Description

The field of technology to which the invention belongs

The present invention provides chemical compounds (e.g., a compound or pharmaceutically acceptable salt and/or hydrate and/or co-crystal and/or combination of a compound) that modulate (e.g., agonize or partially agonize) NLRP3 that are useful, for example, for treatment of a condition, disease, or disorder in which enhancement of NLRP3 signaling can correct a deficiency in innate immune system activity that contributes to the pathology and/or symptoms and/or progression and/or treatment-resistant condition, disease, or disorder (e.g., cancer with low T cell infiltration) in a subject (eg, human). This disclosure also provides compositions, as well as other methods for their use and manufacture.

Prerequisites for the creation of the invention

Nucleotide oligomerization domain-like receptors (NLRs) include a family of intracellular receptors that detect pathogen-associated molecular structures (PAMPs) and endogenous molecules (see, e.g., Ting, J. P. Y. et al., The NLR gene family : a standard nomenclature, Immunity, 28(3): 285-287, (2008)).

NLRPs are a subfamily of NLRs that include a pyrin domain and are composed of proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, and NLRP12. NLRPs are believed to be involved in the formation of multiprotein complexes called inflammasomes (see, e.g., Chaput, C. et al., NODlike receptors in lung diseases, Frontiers in Immunology, 4: article 393, (2013)). These complexes typically include one or two NLR proteins, an adapter apoptosis-associated Speck-like protein containing the CARD domain (ASC) and pro-caspase-1 F (see, e.g., Bauernfeind, F and Hornung, V. Of inflammasomes and pathogens- sensing of microbes by the inflammasome, EMBO Molecular Medicine, 5(6): 814-826, (2013)).

One such inflammasome is formed by the NLRP3 scaffold, ASC adapter, and procaspase-1 (see, e.g., Hirota, J.A., et al., The airway epithelium nucleotide-binding domain and leucine-rich repeat protein 3 inflammasome is activated by urban particulate matter, Journal of Allergy and Clinical Immunology, 129(4):1116.e6-1125.e6, (2012)), and its expression is believed 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 proIL-18 to IL-1e and IL-18. In addition, IL-1e and IL-18 have the potential to treat various types of cancer (see, for example, 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 overcome resistance to checkpoint inhibitors in animal tumor models of colon cancer (see, for example, Ma, Z. et al., Clin. Cancer Res. Jan 11. (2016) DOI:10.1158/1078 -0432.CCR-15-1655).

Brief description of the invention

The invention is directed to compounds of formula (I):

where all variables are as defined below in this document.

Also within the scope of the invention are the pharmaceutically acceptable salts, stereoisomers, tautomers and solvates of the compounds of formula (I).

The invention is also directed to pharmaceutical compositions containing one or more compounds of the invention. The invention is also directed to methods of treating cancer using one or more of the compounds of the invention.

The invention also provides methods and intermediates for the preparation of compounds of formula (I) or their pharmaceutically acceptable salts, stereoisomers, tautomers and solvates.

The compounds of the invention can be used in therapy.

The compounds of the present invention can be used in the manufacture of a medicament for the treatment of cancer.

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 agent(s).

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

- 1 042018

Detailed description of the invention

Compounds according to the invention.

In a first aspect, the present invention provides a compound of formula (IIIb-1):

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ² is independently selected from H, C _1-4 alkyl substituted with 0-3 F, -(CH ₂ ) _1-2 CH(OH)CH ₂ F, -(CH ₂ )i- ₂ CH(OH)CF3, - (CH2)i-2CH(OH)CH2CF3, -(CH2)i-2OCHF2, -(CH2)1-3OCF3, -(CH2)1-2OCH2CF3, -(CH2)2-5OH, -(CH2)2-5CN , -(CH2)1-2CH(CH3)OH, -( _CH2 ) _1-2CH ( _CH3 ) _CH2OH , -(CH2)1-2C(CH3)2OH,

- C (CH3) 2 (CH ₂ ) _1-2 OH, - (CH ₂ ) _1-2 C (CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH (OH )(C _1-4 alkyl),

-CH(CH3)(CH2)1-2OH,-CH2CH(C1-2alkyl)(CH2)1-2OH,-CH2CH(C1-4alkoxy)(CH2)1-2OH,-(CH^OCC-alkyl substituted 0-2 R ^e ), -(CH ₂ ) 1- ₂ CH (CH3)O (C1-4 alkyl), -<CH ₂ ) 1- ₂ C (CH3O (C1.4 alkyl),

- CH (CHz) (CH ₂ ) 1- ₂ O (C1.4 alkyl), -CH ₂ CH (OH) (CH ₂ ) 1- ₂ O (C 1-4 alkyl), -<CH ₂ ) 1- ₂ CH< CHz) NH ₂ , -CH ₂ C (CH ₃ bKH ₂ , - (CH 2) 2-3 NH (C 1-4 alkyl), - (CH ₂ b ^ (C 1.4 alkyl b, -<CH ₂ ) 1-3 C < O) NH ₂ , -(CH ₂ ) 1- ₂ C (CH ₃ LSOCH ₂ ,

- (CH ₂ ) ₁ . ₂ C(O)NH(C _1.4 alkyl substituted with 0-2 R ^e ), -(CH ₂ ) _1-2 C(O)N(CH _{3 )} (C _1-4 alkyl substituted with 0-2 R ^e ), -(CH2)o-1CH(CH3)(CH2)o-1C(O)NH(C1-4alkyl), -(CH2)1-2C(O)N(C1-4alkyl)2,

- (CH2)o-1CH(CH3)C(O)N(C1-4alkyl)2, -(CH2)1-2C(O)N(C1-2αkyl)(CH2)2O(C1-4alkyl), -( CH2)2-3NHC(O)R ^a , -(CH2)1-2CH(CH3)NHC(O)R ^a , -CH2C(CH3^HC(O^ ^a , -(CH2)2-3N(CH3)C (O)R ^a , -(CH2)2-3S(O)2(C1-4αkyl), -CH ₂ CH(CH ₃ )S(O) ₂ (C _1-4 αkylα), -(CH ₂ ) _{2 -3} NHS(O) ₂ (C _1-4 alkyl), -CH ₂ CH (CH ₃ )NHS(O) ₂ (C _1-4 alkyl),

- (CH ₂ ) _2-3 NHS(O) ₂ (C _3-6 cycloαkyl),

-(CH ₂ ) _1-3 -(heteroaryl containing from 5 to 10 ring atoms, with 1 to 4 ring atoms, each independently selected from N, N(R ^f ), O and S), and the specified heteroaryl substituted with 0-2 R ^d ;

R ³ is independently

R ⁴ is independently H or F;

R ^a is independently C1-4 alkyl substituted with 0-1 R ^e , C3-6 cycloalkyl substituted with 0-2 R ^d ,

phenyl or heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl and pyrazinyl, wherein said phenyl and heteroaryl are substituted with 0-2 R ^d ;

R ^d at each occurrence is independently selected from: F, C1, OH, SI, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, IN ₂ , I(C _1-4 alkyl) ₂ , -INS (O)(C _1-4 alkyl) and phenyl;

R ^e is independently selected from F, OH and C _1-4 alkoxy; And

R ^f at each occurrence is independently selected from: H, C _1-4 alkyl, -C(O)(C _1-4 alkyl), and -C(O)(C _1-4 haloalkyl).

- 2 042018

In a twelfth aspect, within the scope of the eleventh aspect, the invention provides a compound of formula (IIIb-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ² is independently selected from H, C _1-4 αalkyl substituted with 0-3 F, -(CH ₂ ) _1-2 CH(OH)CH ₂ F, -(CH2)1-2CH(OH)CF3, -(CH2 )i-2CH(OH)CH2CF3, -(CH ₂ )1. ₂ OCHF ₂ , -(CH2)i-3OCF3, -(CH ₂ )1. ₂ OCH ₂ CF3, -(CH2)2-4OH, -(CH2)2-4CN, -(CH2)1-2CH(CH3)OH, -(CH2)1-2CH(CH3)CH2OH, -(CH2)1 -2C(CH3)2OH, -C(CH3)2(CH2)1-2OH, -(CH2)1-2C(CH3)2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C1-4alkyl),

- CH (CH ₃ ) (CH ₂ ) _1-2 OH, -CH ₂ CH (C _1-2 αlkula) (CH ₂ ) _1-2 OH, -CH ₂ CH (C _1-4 αlkoxy) (CH ₂ ) _1-2 OH, -(CH ₂ ) _2-4 O(C _1-4 alkyl substituted with 0-1 R ^e ), -(CH ₂ ) _1-2 CH(CH ₃ )O(C _1-4 alkyl) , -(CH ₂ ) _1-2 C (CH ₃ ) ₂ O (C _1-4 alkyl),

- CH (CH3) (CH2) 1-2O (C1-4 alkyl), -CHSCHOHCHSHCHf ^ OSH malalkyl), - (CHCHSCHNz ^ SC -CH ₂ C (CH ₃ ) 2NH ₂ , - (CH2) 2-3NH (C1-4 alkyl) ), -(C^^CmalkylaX, 4CH ₂ ) _W C(O)NH ₂ , -(C^^QC^hCON^,

- (CH ₂ ) _1-2 C (O) NH (C _1-4 alkyl substituted with 0-2 R ^e ), - (CH 2) 1-2C (O) N (CH 3) (C 1-4 alkyl substituted with 0- 2 R ^e ), -(CH2) _0-1 CH(CH ₃ )(CH ₂ ) _0-1 C(O)NH(C _1-4 alkyl), -(CH ₂ ) _1-2 C(O)N (C _1-4 alkyl) ₂ ,

- (CH ₂ ) _0-1 CH (CH ₃ ) C (O) N (C _1-4 alkyl) ₂ , - (CH ₂ ) _1-2 C (O) N (C _1-2 alkyl) (CH ₂ ) ₂ O (C _1-4 alkyl), -(CH ₂ ) _2-3 NHC(O)R ^a , -CH2CH(CH3)NHC(O)R ^a , -CH2C(CH ₃ ) ₂ NHC(O)R ^a , -(CH ₂ ) _2-3 S(O) ₂ (C _1-4 αkila), -CH ₂ CH(CH ₃ )S(O) ₂ (C _1-4 αkila), -(CH ₂ ) _{2 -3} NHS(O) ₂ (C _1-4 αkyl), -CH ₂ CH(CH ₃ )NHS(O) ₂ (C _1-4 αkyl), -(CH ₂ ) _2-3 NHS(O) ₂ ( C _3-6 cycloalkyl),

and -(CH ₂ ) _1-2 (heteroaryl), where heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl and pyridazinyl, and heteroaryl is substituted with 0-2 Rd;

R ^a is independently C _1-4 αkyl substituted with 0-1 R ^e ,

phenyl or heteroaryl selected from oxazolyl, pyridyl and pyrazinyl, wherein said phenyl and heteroaryl are substituted with 0-2 R ^d ; And

R ^d at each occurrence is independently selected from: F, Cl, CN, C _1-4 alkyl, C _1-4 alkoxy, and C 1 _-4 haloalkyl.

In a second aspect, within the scope of the eleventh or twelfth aspects, the invention provides a compound of formula (IIIb-1), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ³ is independently

In a third aspect, the invention provides a compound of formula (IIIb-2),

- 3 042018 nh ₂

VN-R ²

C ιΓ

HN' ^N (IIIb-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt, where

R ² is independently selected from H, C _1-4 alkyl substituted with 0-3 F, -(CH ₂ ) _2-4 OH, -(CH ₂ ) _2-4 CN, -(CH ₂ ) _1-2 CH(CH ₃ ) OH, -(CH ₂ ) _1-2 C (CH ₃ ) ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH (OH) (C _1-4 alkyl),

- CH (CH3) (CH2) 1-2OH, -CH2CH (C1-2 alkyl) (CH2) 1-2OH, -ODSad ^ alkoxyCHSCH ^ OH,

- (CH ₂ ) _2-4 O (C _1-4 alkyl substituted with 0-2 R ^e ), -CH ₂ C (CH ₃ ) ₂ NH ₂ , -(CH ₂ ) _1-3 C (O) NH ₂ , -(CH ₂ ) _1-2 C(CH ₃ ) ₂ CONH ₂ , -(CH2)1-2C(O)NH(C1-4alkyl), -(CH2)o-1CH(CH3)(CH2)o- 1C(O)NH(C1-4alkylα), -(CH2)1-2C(O)N(C1-4alkyl)2, -(CH2)o-1CH(CH3)C(O)N(C1-4alkyl)2 , -(CH2)1-2C(O)NH(C1-4alkyl substituted with 0-2 R ^e ),

- (CH ₂ ) _1-2 C(O)N(CH ₃ )(C _1-4 alkyl substituted with 0-2 R ^e ), -CH ₂ CH(CH ₃ )NHC(O)(C _1-4 alkyl ),

- (CH ₂ ) _2-3 S(O) ₂ (C _1-4 alkyl), -CH ₂ CH (CH ₃ )S (O) ₂ (C _1-4 alkyl), -(CH ₂ ) _2-3 NHS(O) ₂ (C _1-4 alkyl),

- CH ₂ CH (CH ₃ )NHS (O) ₂ (C _1-4 alkyl), - (CH ₂ ) _2-3 NHS (O) ₂ (C _3-6 cycloalkyl),

R ^{e is} independently selected from F, OH and C _1-4 alkoxy.

In a fourth aspect, the invention provides a compound of formula (IIIb-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein

R ² is independently selected from H, -CH ₂ CHF ₂ , -(CH ₂ ) _2-4 OH, -(CH ₂ ) _2-4 CN, -CH ₂ CH(CH ₃ )OH, -CH ₂ C(CH ₃ ) ₂ OH,

-CH2CH(OH)CH2OH,

-CH2CH(OH)CH2CH3,

-CH (CH3) (CH2) 2OH,

-CH2CH(CH3)CH2OH,

-CH ₂ CH (OCH3)CH ₂ OH, -(CH2)2O(CH2)2OH, -(CH2)2O(CH2)2OCH3, -CH2C(CH3)2NH2, -(CH2)1-3C(O)NH ₂ ,

-CH ₂ C(CH ₃ ) ₂ CONH ₂ , -(CH ₂ ) _1-2 C(O)NH(CH ₃ ), -(CH ₂ ) _1-2 C(O)NH(CH ₂ CH ₃ ), -(CH ₂ ) _1-2 C(O)NH(CH(CH ₃ ) ₂ ),

-(CH2)o-iCH(CH3)(CH2)o-iC(0)NH(CH3),

-(CH2)o-iCH(CH3)C(0)N(CH3)2,

-C(CH3)2C(O)NH(CH2CHF2),

-(CH2)1-2C(O)NH(C(CH3)2CH2OH),

-(CH2)o-iCH(CH3)C(0)NH(CH(CH3)2), -(CH ₂ )i- ₂ C(O)N(CH3)2,

-CH2C(O)NH(CH2CHF2), -(CH2)1-2C(O)NH(CH2)2OH, -(CH2)1-2C(O)NH(CH2)2OCH3,

-CH(CH ₃ )C(O)NH(CH ₂ CHF ₂ ),

-CH(CH3)C(O)NH(CH2)2-3OH,

-(CH2)1-2C(O)N(CH3)(CH2)2OCH3,

-(CH ₂ ) _2-3 NHS(O) ₂ CH ₃ ,

-CH2CH(CH3)NHC(O)(CH3), -(CH2)2-3S(O)2CH3, -(CH ₂ ) ₂ -38(O) ₂ CH ₂ CH3,

-CH2CH(CH3)NHS(O)2CH3, -(CH2)2-3NHS(O)2(cyclopropylα),

In another aspect, the invention provides a compound of formula (IIIb):

or its tautomer, or a pharmaceutically acceptable salt, where

- 4 042018

R ² is independently selected from H, C _1-4 αlkylα substituted with 0-3 F, -(CH ₂ ) _1-2 CH(OH)CF ₃ , -CH ₂ CH(CH ₃ )NHC(O)(C _{1- 4} alkyl), -CH ₂ C(CH ₃ ) ₂ NHC(O)(C _1-4 alkyl), -(CH ₂ ) _2-3 NHC(O)R ^a ,

- (CH2)2-3NHC(O)CF(CH3)2, -(CH2)2-3N(CH3)C(O)R ^a , -(CH2)2-3OH, -(CH2)1-2CH(CH3 )OH, -(CH2)1-2C(CH3)2OH, -CH2CH(OH)CH2OH, -CH(CH3)(CH2)1-2OH, -(CH2)2-4O(C1-4alkyl), -CH2CH( CH3)NH2, -CHiQC^NHi, -(CH ₂ ) _2-3 NH(C _1-4 alkylα), -(CH ₂ ) _2-3 N(C _1-4 alkyl) ₂ , -(CH ₂ ) _{2 -3} NHS(O) ₂ (C _1-4 alkyl), -(CH ₂ ) _2-3 S(O) ₂ (C _1-4 alkyl),

-(CH ₂ ) _1-3 (heteroaryl), wherein heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl and pyridyl, and heteroaryl is substituted with 0-2 R ^d ;

R ³ is independently

R ^a is independently C _1-4 alkyl, C _3-6 cycloalkyl,

, phenyl or heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl and pyrazinyl, wherein said phenyl and heteroaryl are substituted with 0-2 R ^d ;

R ^d at each occurrence is independently selected from: F, Cl, CN, C _1-4 alkylα, C _1-4 alkoxy, C _1-4 haloalkyl, and phenyl; And

R ^f at each occurrence is independently selected from: H, C _1-4 alkyl, C(O)(C _1-4 alkyl), and C(O)(C _1-4 haloalkyl).

In another aspect, within the scope of the above aspect, the invention provides a compound of formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein

R ² independently selected

- CH ₂ C(CH ₃ ) ₂ NHC(O)(C _1-4 alkyl), from H, C _1-4 alkyl,

-(CH2)2-3NHC(O)R ^a ,

-(CH2)1-2CHF2,

-(CH2)2-3OH,

-(CH2)i-2CH(OH)CF3,

-(CH2)1-2CH(CH3)OH,

-(CH2)1-2C(CH3)2OH, -CH2CH(OH)CH2OH, -CH(CH3)(CH2)1-2OH, -(CH2)2-4O(C1-4alkyl), -CH2CH(CH3)NH2 ,

-(CH ₂ ) 2 _-3 NHS (O) 2 (C _1-4 alkyl),

-CH ₂ C(CH ₃ ) ₂ NH ₂ , -(CH ₂ ) _2-3 NH(C _1-4 alkyl), -(CH ₂ ) _2-3 N(C _1-4 alkyl) ₂ ,

-(CH2)2-3S(O)2(C1-4alkyl),

R ^a is independently C _1-4 alkyl,

- 5 042018 phenyl or heteroaryl selected from oxazolyl, pyridyl and pyrazinyl, where said phenyl and heteroaryl are substituted with 0-2 R ^d .

In another aspect, within either of the above two aspects, the invention provides a compound of formula (IIIb), or a tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is independently

In another aspect, the invention provides a compound selected from the exemplary compounds, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from the compounds of Examples 1151, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from the compounds of Examples 1285, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from the compounds of Examples 1624, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound selected from

- 6 042018

- 7 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt.

- 8 042018

In another aspect, the invention provides a compound selected from

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

- 9 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

- 10 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

- 11 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

- 12 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

- 13 042018

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

or its stereoisomer, tautomer or pharmaceutically acceptable salt. In another aspect, the invention provides a compound selected from

or its stereoisomer, tautomer or pharmaceutically acceptable salt.

In another aspect, the present invention provides a compound selected from any subset of compounds, or one compound from exemplary compounds within any of the above aspects.

The skilled artisan will appreciate that some of the chemical structures described herein may be represented on paper by one or more other resonant forms; or may exist in one or more other tautomeric forms, even if the kinetic expert recognizes that such tautomeric forms represent only a very small fraction of the sample of such compound(s). Such compounds are expressly contemplated within the scope of this invention, although such resonance forms or tautomers are not explicitly represented herein.

Other aspects and embodiments of the invention.

In one aspect, methods for modulating (e.g., agonizing, partially agonizing, antagonizing) NLRP3 activity are provided, which include contacting

- 14 042018

NLRP3 with a chemical compound described herein (eg, a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or compositions containing them). In preferred embodiments, methods for modulating NLRP3 activity are agonizing and partially agonizing. In some embodiments, methods for modulating NLRP3 activity are agonizing. In some embodiments, methods for modulating NLRP3 activity are partially agonizing. The methods include in vitro methods, such as contacting a sample that includes one or more cells containing NLRP3 (eg, THP-1 cells) with a chemical compound. The methods may also include in vivo methods; e.g., administering a chemical compound to a subject (e.g., human) having a disease in which increased NLRP3 signaling can correct a deficiency in innate immune activity that contributes to pathology and/or symptoms and/or disease progression (e.g., cancer; e.g., refractory cancer).

In some embodiments, the compounds of the invention are useful in the treatment of a condition, disease, or disorder in which a decrease in NLRP3 activity (e.g., a condition, disease, or disorder associated with suppressed or impaired NLRP3 signaling) contributes to pathology and/or symptoms, and/ or the progression of a condition, disease, or disorder (eg, cancer) in a subject (eg, human).

A cancer is considered refractory if it does not respond to cancer treatment (or is resistant to cancer treatment). Refractory cancer is also known as resistant cancer.

In another aspect, methods of treating cancer are provided which comprise administering to a subject in need of such treatment 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 compositions). In some embodiments, the cancer may be a refractory cancer.

In a further aspect, methods are provided for treating a disease wherein enhancing NLRP3 signaling can correct a deficiency in innate immune activity that contributes to the onset of pathology and/or symptoms and/or disease progression, which comprises administering to a subject in need of such treatment an effective amount of a chemical compound. described herein (eg, a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or compositions containing them).

In another aspect, methods of treatment are provided which comprise administering to a subject having a disease in which an increase in NLRP3 signaling can correct a deficiency in innate immune system activity that contributes to pathology and/or symptoms and/or disease progression, an effective amount of a chemical compound described herein (eg, a compound described herein generally or specifically, or a pharmaceutically acceptable salt thereof, or compositions containing them).

In a further aspect, methods of treatment are provided that include administering to a subject a chemical compound described herein (e.g., a compound described generally or specifically herein, or a pharmaceutically acceptable salt thereof, or compositions containing the same), wherein the chemical compound is administered to an amount that is effective for treating the disease, in which the enhancement of NLRP3 signaling can correct the deficiency in the activity of the innate immune system that contributes to the occurrence of pathology and/or symptoms and/or disease progression, thereby treating the disease.

Embodiments may include one or more of the following features.

The chemical compound may be administered in combination with one or more additional cancer treatments (e.g., surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, or gene therapy, or a combination thereof; for example, cancer treatments that include administering one or more (e.g., two, three, four, five, six, or more) additional anti-cancer agents Non-limiting examples of additional anti-cancer agents (chemotherapeutic agents) are selected from an alkylating agent (e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin ); antimetabolite (eg azathioprine and/or mercaptopurine); terpenoid (eg vinca alkaloid and/or taxane; eg vincristine, vinblastine, vinorelbine and/or vindesine, taxol, paclitaxel and/or docetaxel); topoisomerases (eg topoisomerase type I and/or type 2 topoisomerase; for example, camptothecins such as irinotecan and/or topotecan; amsacrine, etoposide, etoposide phosphate and/or teniposide); a cytotoxic antibiotic (eg, actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, bleomycin, plicamycin, and/or mitomycin); a hormone (eg, a luteinizing hormone-releasing hormone agonist; eg, leuprolidine, goserelin, triptorelin, gistrelin, bicalutamide, flutamide, and/or nilutamide); antibodies (eg, abciximab, adalimumab, alemtuzumab, atlizumab, basiliximab, belimumab, bevacizumab, bretuximab vedotin, canakinumab, cetuximab, certolizumab pegol, daclizumab, denosumab, eculizumab

- 15 042018 mab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromoHa6-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumuab, ranibizumab, rituximab, tocilizumab, tositumumab and/or trastuzumab); an anti-angiogenic agent; cytokine; thrombotic agent; a growth inhibitory agent; antihelminthic; and an immune checkpoint inhibitor that targets an immune checkpoint receptor 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 protein 3 (LAG3), MHC class IILAG3 ligand, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR-GITR ligand , 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, CD48CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophylins including BTNL2, Siglec family, TIGIT family members and PVR , KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, phosphatidylserine, TIM3, phosphatidylserine-TIM3, SIRPA-CD47, VEGF30, neurophilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1) and other immunomodulatory agents, such as interleukin-2 (IL-2), indolamine-2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFe), CD39, CD73, adenosine-CD39-CD73 and CXCR4-CXCL12.

The subject may have cancer; for example, the subject has been and/or is and/or will be undergoing one or more cancer treatments.

Non-limiting examples of cancer include acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, cancer eye, fallopian tube cancer, gallbladder 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 , larynx cancer, chronic myelogenous leukemia, lip cancer and oral cavity, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oropharyngeal cancer, oral cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, cancer small intestine, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer.

In other embodiments, the mammal has been diagnosed with cancer or an infectious disease. Typical infectious diseases include, without limitation, Acinobacter infection, actinomycosis, African sleeping sickness, acquired immunodeficiency syndrome, amoebiasis, anaplasmosis, anthrax, Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus infections cereus, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balantidiasis, Baylisascaris infection, BK virus infection, black piedra, Blastocystic hominis infection, blastomycosis, Bolivian hemorrhagic fever, botulism, Brazilian hemorrhagic fever, brucellosis, bubonic plague, Burkholderi infection, Buruli ulcers, calicivirus infection, camptobacteriosis, candidiasis, cat-scratch disease, cellulitis, Chagas disease, chancroid, chickenpox, chikungunya, chlamydia, Chlamydophila pneumoniae infection, cholera, chromoblastomycosis, clonorchiasis, Clostridium difficile infection, coccidioidomycosis, colora tick fever, common cold, Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, critococcosis, cryptosporidiosis, wandering larva skin syndrome, cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever, Desmodesmus infection, deintamebiasis, diphtheria, diphyllobothriasis, dracunculiasis, hemorrhagic fever , echinococcosis, ehrlichiosis, enterobiasis, Enterococcus infection, Enterovirus infection, epidemic typhus, infectious erythema, sudden exanthema, fasciolopsiosis, fascioliasis, fatal familial insomnia, filariasis, Clostridium myonecrosis food poisoning, free-living amoebae infection, Fusobacterium infection, gas gangrene, geotrichosis, syndrome Gerstmann-Straussler-Scheinker, gardiasis, glanders, gnathostomiasis, gonorrhea, granuloma inguinal, group A streptococcal infections, group B streptococcal infections, Haemophilus influenzae infection, hand-foot-mouth syndrome, hantavirus pulmonary syndrome, Heartland virus disease, Heliobacter infection er pylori, 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, human parainfluenza virus infection, hymenolepiasis, Epstein-Barr infectious mononucleosis, influenza, isosporosis, Kawasaki disease, keratitis, Kingella kingae infection, kuru, Laotian fever, le

- 16 042018 hyonellosis, Pontiac fever, leishmaniasis, leprosy, leptospirosis, listeriosis, Lyme disease, lymphatic filariasis, lymphocytic choriomeningitis, malaria, Marburg hemorrhagic fever, measles, Middle East respiratory syndrome, melioidosis, meningitis, meningococcal infection, metagonimiasis, microsporidiosis mollusks , monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma, myiasis, neonatal conjunctivitis, Creutzfeldt-Jakob disease variant, nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis, pasteurellosis, pediculosis of the scalp, underwear pediculosis, pubic pediculosis, inflammatory diseases pelvic organ disease, whooping cough, plague, pneumonia, poliomyelitis, Prevotella infection, primary amoebic meningoencephalitis, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, rat bite fever, respiratory syncytial virus infection, rhinosporidiosis, rhinovirus infection, RI rickettsial infection, smallpox rickettsiosis, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonellosis, severe acute respiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis, shingles, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis , subacute sclerosing leukoencephalitis, syphilis, teniasis, stoblitis, trichophytosis of the beard and mustache area, trichophytosis of the scalp, trichophytosis of the body, trichophytosis of the inguinal and axillary region, trichophytosis of the palms and hands, black lichen, trichophytosis of the foot, onychomycosis dermatophytosis, versicolor versicolor, toxocariasis, trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichiuriasis, tuberculosis, tularemia, Ureaplasma urealyticum infection, Venezuelan equine encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white piedra, Yersinia psuedotuberculosis infection, yerseniasis, yellow fever, and zygomycosis.

The chemical compound can be administered intratumorally.

The chemical compound can be administered systemically (including, but not limited to, orally, subcutaneously, intramuscularly, intravenously).

The methods may further include identifying the subject.

Other embodiments include those described in the Detailed Description and/or the claims.

Definitions.

To facilitate understanding of the invention set forth herein, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures described in the fields of organic chemistry, medicinal chemistry, and pharmacology are well known and widely used in the art. Unless otherwise indicated, all technical and scientific terms used herein generally have the same meaning as generally understood by a person skilled in the art to which this invention pertains.

Unless specifically stated herein, references made in the singular may also include the plural. For example, they can refer to one or one or more.

Unless otherwise stated, any heteroatom with unsaturated valences is assumed to have enough hydrogen atoms to saturate the valences.

For the purposes of clarity, and in accordance with standard rules in the art, the symbol I is used in formulas and tables to indicate a bond, which is the point of attachment of a moiety or substituent to the center/core of the structure.

In addition, for clarity, when a substitute has a dash (-) not between two letters or characters; this is used to indicate the point of attachment for a substituent. For example, -OCH3 is attached via an oxygen atom.

As used herein, the term NLRP3 is intended to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants , derivatives, splicing variants, alleles, various species and their active fragments.

An NLRP3 agonist includes compounds that, at the protein level, directly bind or modify NLRP3 in such a way that NLRP3 activity is increased, for example, by activation, stabilization, distribution change, or otherwise.

Certain compounds described herein that agonize NLRP3 to a lesser extent than a full NLRP3 agonist may function as antagonists as well as agonists in assays. These compounds antagonize NLRP3 activation by a full NLRP3 agonist because they prevent the full effect of interaction with NLRP3. However, the compounds also themselves activate some NLRP3 activity, usually less than the corresponding amount of a full NLRP3 agonist. Such compounds may be referred to as NLRP3 partial agonists.

In some embodiments, the compounds described herein are

- 17 042018 NLRP3 agonists (eg full agonists). In other embodiments, the compounds described herein are NLRP3 partial agonists.

As a rule, the receptor exists in active (Ra) and inactive (Ri) conformation. Some compounds that affect the receptor can change the ratio of Ra to Ri (Ra/Ri). For example, a full agonist increases the Ra/Ri ratio and can produce a maximal satiety effect. A partial agonist, when bound to a receptor, produces a lower response than that elicited by a full agonist (eg, an endogenous agonist). Thus, the Ra/Ri for a partial agonist is less than for a full agonist. However, the effectiveness of a partial agonist may be greater or less than that of a full agonist.

As used herein, the term "acceptable" in relation to a formulation, composition, or ingredient means that there is no persistent adverse effect on the general health of the subject being treated.

API refers to the active pharmaceutical ingredient.

As used herein, the terms effective amount or therapeutically effective amount refer to a sufficient amount of a chemical compound (e.g., a compound exhibiting activity as a mitochondrial uncoupler, or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal thereof; e.g., compounds, such as niclosamide, or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal thereof; e.g., a compound such as a niclosamide analog, or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal thereof), which will weaken to some extent one or more symptoms of the disease or condition being treated. The result includes the reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired change in the biological system. For example, an effective amount for therapeutic applications is the amount of a composition containing a compound disclosed herein required to provide a clinically significant reduction in the symptoms of a disease. An appropriate effective amount in each individual case may be determined using any suitable method, such as a dose escalation study.

The term excipient or pharmaceutically acceptable excipient means a pharmaceutically acceptable material, composition, or carrier such as a liquid or solid excipient, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is pharmaceutically acceptable in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with a human or animal tissue or organ without undue toxicity, irritation, allergic reaction, immunogenicity, or other problems or complications. commensurate with a reasonable benefit/risk ratio. See, 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 Pharmaceutical Association: (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).

The term pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not alter the biological activity and properties of the compound. In some instances, pharmaceutically acceptable salts are prepared by reacting a compound described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and etc. In some cases, pharmaceutically acceptable salts are prepared by reacting a compound having an acidic group as described herein with a base to form a salt such as an ammonium salt, an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium salt or magnesium, an organic base salt such as dicyclohexylamine, N-methylD-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously defined. The pharmacologically acceptable salt is not particularly limited as long as it can be used in medicines. Examples of the salt that the compounds described herein form with a base include the following: their salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; their salts with organic bases such as methylamine, ethylamine and ethanolamine; their salts with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts formed with the following: mineral 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

- 18 042018 ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

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 thickeners. The pharmaceutical composition facilitates the administration of the compound to the body. There are many routes of administration of a compound in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term subject refers to an animal, including, but not limited to, primates (eg, humans), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms subject and patient are used interchangeably herein with respect to, for example, a mammal such as a human.

The terms treat, treatment, and therapy, in the context of treating a disease or disorder, mean alleviating or eliminating the disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more of its symptoms. Cancer treatment refers to one or more of the following effects: (1) inhibition, to some extent, tumor growth, including (i) slowing and (ii) complete arrest of growth; (2) reduction in the number of tumor cells; (3) maintenance of tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete cessation of infiltration of tumor cells into peripheral organs; (6) inhibition, including (i) reduction, (ii) delay or (iii) complete cessation of metastasis; (7) enhancement of the antitumor immune response, which may result in (i) maintenance of tumor size, (ii) reduction in tumor size, (iii) slowing of tumor growth, (iv) reduction, slowing or prevention of invasion, and/or (8) alleviation to some extent, the severity or number of one or more symptoms associated with the disorder.

The term halo refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

The term alkyl refers to a hydrocarbon chain, which may be straight or branched chain, containing the specified number of carbon atoms. For example, C1_ ₁₀ indicates that the group may contain from 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, t-butyl, n-hexyl.

The term alkylene refers to a branched or straight chain divalent alkyl (eg -CH2-).

The term haloalkyl refers to alkyl in which one or more hydrogen atoms have been replaced by an independently selected halo.

The term alkoxy refers to an -O-alkyl radical (eg -OCH3).

The term haloalkoxy refers to a -O-haloalkyl group, as defined above, with the number of carbon atoms indicated via an oxygen bridge. For example, _C1 . ₆ haloalkoxy includes C1, _C2 , _C3 , _C4 , _C5 and _C6 haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.

The term alkenyl refers to a hydrocarbon chain, which may be straight or branched chain, having one or more carbon-carbon double bonds. The alkenyl fragment contains the indicated number of carbon atoms. For example, C ₂ - ₆ indicates that the group may contain from 2 to 6 (inclusive) carbon atoms.

The term alkynyl refers to a hydrocarbon chain, which may be a straight or branched chain having one or more carbon-carbon triple bonds. The alkynyl fragment contains the indicated number of carbon atoms. For example, C ₂ - ₆ indicates that the group may contain from 2 to 6 (inclusive) carbon atoms.

The term aromatic generally refers to a ring that includes a cyclic array of resonantly stabilized 4n+2 pi electrons, where n is an integer (eg, 1 or 2). Aromatic moieties include aryl and heteroaryl groups. The term non-aromatic describes any moiety that does not fall within the definition of aromatic.

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 may be substituted with a substituent, and where the ring containing the monocyclic radical is aromatic, and wherein at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic, eg tetrahydronaphthyl. Examples of aryl groups also include phenyl, naphthyl, and the like.

As used herein, the term cycloalkyl includes saturated cyclic hydrocarbon groups containing 3-10 carbon atoms, preferably 3-8 carbon atoms, and more preferably 3-6 carbon atoms, wherein the cycloalkyl group may optionally be

- 19 042018 substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. As used herein, the term cycloalkylene refers to divalent cycloalkyl.

The term heteroaryl refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system having 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic or 1-9 heteroatoms in in the case of tricyclic, wherein said heteroatoms are selected from O, N, or S (for example, carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms in the case of monocyclic, bicyclic, or tricyclic, respectively), where 0 , 1, 2, 3, or 4 atoms of each ring may be substituted with a substituent, and where the ring containing the monocyclic radical is aromatic, and where at least one of the fused rings containing the bicyclic or tricyclic radical is aromatic (but need not be be a ring which contains a heteroatom, such as tetrahydroisoquinolinyl.Examples of heteroaryl groups also include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienium l, quinolinyl, indolyl, thiazolyl, and the like.

The term heterocyclyl refers to a non-aromatic 5-8 membered monocyclic, 7-12 membered bicyclic or bridged, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, spiro or bridged , or 1-9 heteroatoms in the case of tricyclic, while said heteroatoms are selected from O, N or S (for example, carbon atoms and 1-3, 1-6 or 1-9 heteroatoms N, O or S in the case of monocyclic, bicyclic or tricyclic, respectively), where 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. The term heterocycloalkylene refers to a divalent heterocyclyl.

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

A detailed description of one or more embodiments of the invention is presented in the accompanying drawings and in the description below. Other features and advantages of the invention will be apparent from the description and drawings, as well as from the claims.

This invention provides chemical compounds (e.g., a compound or a pharmaceutically acceptable salt and/or hydrate and/or co-crystal and/or compound-drug combination thereof) that modulate (e.g., agonize or partially agonize) NLRP3 that are useful for example, to treat a condition, disease, or disorder in which increased NLRP3 signaling can correct a deficiency in innate immune system activity (e.g., a condition, disease, or disorder associated with an inadequate immune response) that contributes to the pathology and/or symptoms, and/ or the progression of a condition, disease, or disorder (eg, cancer) in a subject (eg, human). In addition, this invention provides compositions, as well as other methods of their use and manufacture.

Pharmaceutical compositions and administration.

In some embodiments, a 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 co-crystal and/or drug combination thereof) is administered as a pharmaceutical a composition that includes a chemical compound and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents, as described herein.

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

In some embodiments, the chemical compounds may 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 systems (SEDDS) such as d-a-tocopherol, polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as tweens, poloxamers or other similar polymeric delivery matrices, whey proteins such as che

- 20 042018 human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, dibasic sodium phosphate, potassium hydrogen phosphate, chloride sodium, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes of various kinds, polyethylene and polyoxypropylene block polymers, and lanolin. Cyclodextrins such as α- and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives, may also be used to improve delivery of the compounds described herein. Can be made dosage forms or compositions containing the chemical compound described herein, in the range of 0.005-100%, while the balance consists of a non-toxic excipient. Contemplated compositions may contain 0.001-100% of the chemical compound provided herein, in one embodiment 0.195%, in another embodiment 75-85%, in a further embodiment 20-80%. The actual methods for making such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, ^22nd Edition (Pharmaceutical Press, London, UK. 2012).

Methods of administration and components of the composition.

In some embodiments, the chemical compounds described herein, or a pharmaceutical composition 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, buccal, dermal, endocervical, endo-sinus, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intra-bronchial, intra-bursal, intra-cerebral, intra-cisternal, intra-coronary, intra-dermal, intra-ductal. intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intrailiac, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intravascular, intravascular, nasal, nasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In some embodiments, the preferred route of administration is parenteral (eg intratumoral). In some embodiments, the preferred route of administration is systemic.

The compositions may be formulated for parenteral administration, eg formulated for injection via the intravenous, intramuscular, subcutaneous or even intraperitoneal routes of administration. Typically, such compositions may be formulated as injectables, either as liquid solutions or suspensions; also can be made solid forms suitable for use in the preparation of solutions or suspensions by adding a liquid before injection; and preparations can also be emulsified. The manufacture of such formulations will be known to those skilled in the art in light of the present invention.

Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions; formulations comprising sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the preparation of sterile injectable solutions or dispersions immediately before use. In all cases, the composition must be sterile and must be fluid to the extent that it can be easily administered by injection. It must also be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (eg glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion, and by using surfactants. Protection against the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, such as sugars or sodium chloride. Prolonged absorption of injectable compositions can be achieved by including in the composition agents that delay absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in a suitable solvent with various other ingredients listed above,

- 21 042018 if necessary, followed by filter sterilization. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile carrier which contains the basic dispersion medium and the other necessary ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of manufacture are vacuum drying and lyophilization methods, which allow the preparation of a powder of the active ingredient plus any additional desired ingredient from their previously sterilized filtered solution.

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

Pharmacologically acceptable excipients used in a rectal gel, cream, enema or rectal suppository formulation include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (e.g. PEG ointments), glycerin , glycerinated gelatin, hydrogenated vegetable oils, poloxamers, blends of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petroleum jelly, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, SBN anoxide, ethereal vanilla oil, aerosol, parabens in phenoxyethanol, sodium methyl parahydroxybenzoate, sodium propyl paraoxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy metabisulphite, edetat and sodium, sodium benzoate, potassium metabisulphite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

In some embodiments, suppositories can be made by mixing the chemical compounds described herein with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, the rectal compositions are in the form of an enema.

In other embodiments, the compounds described herein, or a pharmaceutical composition thereof, are suitable for topical delivery to the digestive tract or gastrointestinal tract by oral administration (eg, in solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical compound is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate and/or: a) excipients or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b ) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and gum arabic, c) wetting agents such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite clay, and i) lubricants such as talc, stea calcium rat, magnesium stearate, solid polyethylene glycols, 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 can also be used as fillers in soft and hard gelatin capsules using fillers such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will be in unit dosage form such as a pill or tablet and thus the composition may contain, along with the chemical compound provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like. .; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, and the like. In another solid dosage form, the powder, microgranules, solution or suspension (eg in propylene carbonate, vegetable oils, PEG, poloxamer 124 or triglycerides) is encapsulated (gelatin or cellulose based capsule). Also contemplated are unit dosage forms in which one or more chemical compounds provided herein or additional active agents are physically separated; for example, capsules with granules (or tablets in a capsule) of each drug; bilayer tablets; double chamber gelatin capsules, etc. Also, oral dosage forms are considered.

- 22 042018 enteric coated or sustained release.

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

In some embodiments, the excipients are sterile and generally free of unwanted substances. These compositions can be sterilized by conventional, well known sterilization techniques. For various excipients for oral dosage forms, such as tablets and capsules, sterility is not required. The USP/NF standard is usually sufficient.

In some embodiments, solid oral dosage forms may further include one or more components that chemically and/or structurally assist the composition in delivering the chemical to the stomach or lower GI tract; for example, the ascending colon and/or the transverse colon and/or the distal colon and/or the small intestine. Illustrative formulation techniques are described, for example, in Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper GI targeting methods such as Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower GI targeting techniques. Several enteric/pH sensitive coatings and excipients exist to target different areas of the intestinal tract. These materials are typically polymers that are designed to dissolve or erode within specific pH ranges, selected based on the region of the GI tract that drug release is desired. These materials also protect acid-labile drugs from gastric acid attack or limit exposure where the active ingredient may cause upper GI irritation (e.g., the hydroxypropyl methylcellulose phthalates range, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, the Eudragit series (copolymers of methacrylic acid and methyl methacrylate) and Marcoat). Other methods include dosage forms that respond to local flora in the gastrointestinal tract, the colonic pressure-controlled delivery capsule, and Pulsincap.

Ophthalmic compositions may include, without limitation, any one or more of the following: viscogenes (eg, carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (eg pluronic (triblock copolymers), cyclodextrins); preservatives (eg, benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), purite (stabilized oxychloro complex; Allergan, Inc.)).

Compositions for topical application may include ointments and creams. Ointments are semi-solid preparations that are usually based on petrolatum or other petroleum jelly derivatives. Creams containing the selected active agent are usually viscous liquid or semi-solid emulsions, often either oil-in-water or water-in-oil. Cream bases are usually water-washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes referred to as the internal phase, usually consists of petrolatum 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 usually contains a wetting agent. The emulsifier in a cream is usually a non-ionic, anionic, cationic, or amphoteric surfactant. As with other carriers or excipients, the ointment base must be inert, stable, non-irritating and non-allergenic.

In any of the above embodiments, the pharmaceutical compositions described herein may include one or more of the following components: lipids, cross-linked multilayer vesicles, biodegradable nanoparticles or microparticles based on poly(D,L-lactic-co-glycolic acid) [ PLGA], and lipid bilayers based on nanoporous particles.

Dosages.

Dosages 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 correct dosage for a particular situation can be carried out by a person skilled in the art of medicine. The total daily dose may be divided and administered in portions throughout the day or by providing continuous delivery.

In some embodiments, the compounds described herein are administered at a dose 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 up to about 200 mg/kg, from about 0.01 mg/kg to about 150 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg kg; from approx.

- 23 042018

0.01 mg/kg to about 10 mg/kg; from about 0.01 mg/kg to about 5 mg/kg; from about 0.01 mg/kg to about 1 mg/kg; from about 0.01 mg/kg to about 0.5 mg/kg; from about 0.01 mg/kg to about 0.1 mg/kg; from about 0.1 mg/kg to about 200 mg/kg; from about 0.1 mg/kg to about 150 mg/kg; from about 0.1 mg/kg to about 100 mg/kg; from about 0.1 mg/kg to about 50 mg/kg; from about 0.1 mg/kg to about 10 mg/kg; from about 0.1 mg/kg to about 5 mg/kg; from about 1 mg/kg to about 1 mg/kg; about 0.1 mg/kg to about 0.5 mg/kg).

Introduction modes.

The above dosages may be administered on a daily basis (eg, as a single dose or as two or more divided doses) or on a non-daily basis (eg, every other day, every two days, every three days, once a week, twice a week once every two weeks, once a month).

In some embodiments, the administration period for a compound 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 another embodiment, the period during which administration is stopped 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 one embodiment, the therapeutic compound is administered to the individual over a period of time followed by a separate period of time. In another embodiment, the therapeutic compound is administered during a first period, and the first period is followed by a second period, with administration being stopped during the second period, followed by a third period when administration of the therapeutic compound is started, and then following the third period, a fourth period when administration is stop. In one aspect of this embodiment, the period of administration of the therapeutic compound, followed by the period when the administration is stopped, is repeated for a specified or indefinite period of time. In another embodiment, 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 another embodiment, the period during which administration is stopped 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.

Methods of treatment.

In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased NLRP3 signaling can correct a deficiency in innate immune system activity (e.g., a condition, disease, or disorder associated with a deficient immune response) that contributes to the pathology and/ or symptoms and/or progression of a condition, disease, or disorder (eg, cancer).

Indications for use.

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 has been diagnosed as having cancer.

Non-limiting examples of cancer include: acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer , bronchial tumor, carcinoid tumor, heart tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, eye cancer, fallopian tube cancer, gallbladder 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, cancer kidney, laryngeal cancer, chronic myelogenous leukemia, lip cancer and oral cavity, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oropharyngeal cancer, oral cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer, skin cancer, cancer small intestine, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer.

In some embodiments, non-limiting examples of cancer include: breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, and prostate cancer.

Methods for diagnosing a subject as having cancer or identifying a mammal as having

- 24 042018 cancers are well known in the art. For example, a medical professional (eg, physician, physician assistant, or technician) may diagnose cancer in a mammal by observing one or more symptoms of cancer in the mammal. Non-limiting examples of cancer symptoms include: fatigue, hardness or a felt area of thickening under the skin, weight change, jaundice, darkening or redness of the skin, ulcers that do not heal, changes in existing moles, changes in bowel and bladder behavior, persistent cough or difficulty breathing, difficulty swallowing, hoarseness, persistent indigestion or discomfort after eating, persistent unexplained muscle or joint pain, persistent unexplained fever or night sweats, and unexplained bleeding or bruising. Methods for diagnosing a subject as having cancer or identifying a subject as having cancer may further include performing one or more diagnostic tests (eg, performing one or more diagnostic tests on a biopsy or blood sample).

In some examples of any of the methods described herein, the subject may be a subject having cancer, a subject diagnosed as having cancer, or a subject identified as having cancer who has not responded to a previously administered cancer treatment. Diagnostic tests for diagnosing a subject as having cancer or identifying a mammal as having cancer are known in the art.

In some embodiments, methods are provided for treating a subject having a condition, disease, or disorder in which increased NLRP3 signaling can correct a deficiency in innate immune system activity (e.g., a condition, disease, or disorder associated with a deficient immune response) that contributes to the pathology and/ or symptoms and/or progression of a condition, disease, or disorder (eg, cancer).

In some embodiments, the present invention provides a method of treating cancer, wherein the cancer may be any cancer that does not elicit an optimal response from the innate immune system.

The innate immune system refers to the part of the immune system that is made up of cells that respond to threats to the body, such as infections or cancer, in an antigen-non-specific manner and stimulate an adaptive, antigen-specific immune system. In general, complete elimination of a threat and long-term protection (=immunity) requires the activity of an adaptive, antigen-specific immune system, which in turn depends on stimulation from the innate immune system.

In some embodiments, the present invention provides a method of treatment, wherein the cancer is selected based on resistance to T cell checkpoint inhibition, regardless of cancer type, and based on lack of response to previous therapy with T cell checkpoint inhibitors, or based on cancer type, which is generally resistant to T cell checkpoint inhibitor therapy, such as hormone receptor positive breast cancer, microsatellite stable colon or rectal cancer, pancreatic cancer and prostate cancer.

In some other embodiments, the present invention provides a cancer treatment method comprising an NLPR3 agonist of the present invention for treating non-inflammatory tumors with low CD8+ T cell infiltration to increase tumor immunogenicity and stimulate inflammatory responses. For example, the combination can be used to treat a solid tumor based on biopsy results that demonstrate low infiltration by CD8+ T cells or low expression of genes produced by CD8+ T cells.

Resistance to T cell checkpoint inhibition refers to progression of cancer in response to therapy or failure to respond within 6 months of therapy according to consensus response criteria for the respective cancer, such as RECIST1.1 for most solid tumors.

T cell infiltration refers to the percentage of T cells of all nucleated cells as determined by immunohistochemical analysis of tumor biopsy specimens.

CD8+ T cell infiltration refers to the percentage of CD8+ cells of all nucleated cells as determined by immunohistochemical analysis of tumor biopsy specimens.

In addition to immunohistochemical analysis to quantify CD8+ T cells in biopsy specimens, the expression of genes produced by CD8+ T cells, such as interferon, can be measured by mRNA quantification using, for example, next generation sequencing and provide information on CD8+ T-cell infiltration. cells. Thresholds for low and high CD8+ T cell infiltration by immunohistochemical analysis of mRNA quantification methods are being developed by various groups and take into account the spectrum of CD8+ T cell infiltration in cancers as well as for specific cancers.

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 has been identified as having an infectious disease, or has been diagnosed as having

- 25 042018 infectious disease. For example, an infectious disease may be caused by a bacterium, virus, fungus, parasite, or mycobacterium.

Typical infectious diseases include, without limitation, Acinobacter infection, actinomycosis, African sleeping sickness, acquired immunodeficiency syndrome, amoebiasis, anaplasmosis, anthrax, Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever, ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacillus infections cereus, bacterial pneumonia, bacterial vaginosis, Bacteroides infection, balantidiasis, Baylisascaris infection, BK virus infection, black piedra, Blastocystic hominis infection, blastomycosis, Bolivian hemorrhagic fever, botulism, Brazilian hemorrhagic fever, brucellosis, bubonic plague, Burkholderi infection, Buruli ulcers, calicivirus infection, camptobacteriosis, candidiasis, cat-scratch disease, cellulitis, Chagas disease, chancroid, chickenpox, chikungunya, chlamydia, Chlamydophila pneumoniae infection, cholera, chromoblastomycosis, clonorchiasis, Clostridium difficile infection, coccidioidomycosis, colora tick fever, common cold, Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever, critococcosis, cryptosporidiosis, wandering larva skin syndrome, cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever, Desmodesmus infection, deintamebiasis, diphtheria, diphyllobothriasis, dracunculiasis, hemorrhagic fever , echinococcosis, ehrlichiosis, enterobiasis, Enterococcus infection, Enterovirus infection, epidemic typhus, infectious erythema, sudden exanthema, fasciolopsiosis, fascioliasis, fatal familial insomnia, filariasis, Clostridium myonecrosis food poisoning, free-living amoebae infection, Fusobacterium infection, gas gangrene, geotrichosis, syndrome Gerstmann-Straussler-Scheinker, gardiasis, glanders, gnathostomiasis, gonorrhea, granuloma inguinal, group A streptococcal infections, group B streptococcal infections, Haemophilus influenzae infection, hand-foot-mouth syndrome, hantavirus pulmonary syndrome, Heartland virus disease, Heliobacter infection er pylori, 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, human parainfluenza virus infection, hymenolepiasis, Epstein-Barr infectious mononucleosis, influenza, isosporiasis, Kawasaki disease, keratitis, Kingella kingae infection, kuru, Laotian fever, legionellosis, Pontiac fever, leishmaniasis, leprosy, leptospirosis, listeriosis, Lyme disease, lymphatic filariasis, lymphocytic choriomeningitis, malaria, Marburg haemorrhagic fever, measles, Middle East respiratory syndrome, melioidosis, meningitis, meningococcal disease, metagonimiasis, microsporidiosis, molluscum contagiosum, monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma, m iasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease, nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis, pasteurellosis, head lice, pediculosis underwear, lice pubis, pelvic inflammatory disease, whooping cough, plague, pneumonia, poliomyelitis, Prevotella infection, primary amoebic meningoencephalitis, progressive multifocal leukoencephalopathy, psittacosis, Q fever, rabies, rat bite fever, respiratory syncytial virus infection, rhinosporidiosis, rhinovirus infection, rickettsial infection, smallpox rickettsiosis, Rift Valley fever, Rocky Mountain spotted fever, rotavirus infection, rubella, salmonella severe acute respiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis, herpes zoster, smallpox, sporotrichosis, staphylococcal food poisoning, staphylococcal infection, strongyloidiasis, subacute sclerosing leukoencephalitis, syphilis, taeniasis, tetanus, trichophytosis of the beard and moustache c, trichophytosis of the scalp, trichophytosis of the body, trichophytosis of the inguinal and axillary region, trichophytosis of the palms and hands, black lichen, trichophytosis of the foot, dermatophytic onychomycosis, versicolor versicolor, toxocariasis, trachoma, toxoplasmosis, trichinosis, trichomoniasis, trichiuriasis, tuberculosis, tularemia, infection Ureaplasma urealyticum, Venezuelan equine encephalitis, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever, white piedra, Yersinia psuedotuberculosis infection, yerseniasis, yellow fever, and zygomycosis.

Methods for diagnosing a subject as having an infectious disease or identifying a subject as having an infectious disease are well known in the art. For example, a healthcare professional (eg, a physician, physician assistant, or technician) may diagnose an infectious disease in a subject by observing one or more symptoms of the infectious disease in the subject. Non-limiting examples of symptoms of an infectious disease include fever, diarrhea, fatigue, and muscle pain. Methods for diagnosing a mammal as having an infectious disease or identifying a subject as having an infectious disease may further include performing one or more diagnostic tests (eg, performing one or more diagnostic tests on a biopsy or blood sample). Diagnostic tests for diagnosing a subject as having an infectious disease or identifying a subject as having an infectious disease are known in the art.

Combined therapy.

- 26 042018

The present invention contemplates both monotherapy regimens and combination therapy regimens.

In some embodiments, the methods described herein may further include the administration of one or more additional therapies (eg, one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

In some embodiments, the methods described herein may further include one or more additional cancer treatments.

One or more additional cancer treatments may include, without limitation, surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, cancer vaccines (eg, HPV vaccine, hepatitis B vaccine, Oncophage, Provenge), and gene therapy, and also their combinations. Immunotherapy includes, without limitation, adoptive cell therapy, generation of stem cells and/or dendritic cells, blood transfusion, lavage, and/or other therapies, including, but not limited to, tumor freezing.

In some embodiments, one or more additional cancer treatments are chemotherapy, which may include the administration of one or more additional chemotherapeutic agents.

In some embodiments, the complementary cancer therapy comprises (the chemotherapeutic agent) an immunomodulatory moiety, eg, an immune checkpoint inhibitor. In some of these embodiments, the immune checkpoint inhibitor targets an immune checkpoint receptor 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 (LAG3), MHC class II-LAG3 ligand, 4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR- ligand GITR, CD27, CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40, 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, butyrophylins including BTNL2, Siglec family, family members TIGIT and PVR, KIR, ILT and LIR, NKG2D and NKG2A, MICA and MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28, Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF30, Neurophilin, CD160, CD30 and CD155 (eg CTLA-4 or PD1 or PD-L1) and others their immunomodulatory agents such as interleukin-2 (IL-2), indolamine-2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFe), CD39, CD73, adenosine-CD39-CD73 and CXCR4 -CXCL12. See, for example, Postow, M.J. Clin. oncol. 33, 1 (2015).

In some 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.

In some embodiments, the immune checkpoint inhibitor is selected from: nivolumab (also known as OPDIVO; formerly 5C4, BMS-936558, MDX-1106, or ONO-4538), pembrolizumab (also known as KEYTRUDA, lambrolizumab, and MK-3475. See WO 2008/156712), PDR001 (Novartis; see WO 2015/112900), MEDI-0680 (AstraZeneca; AMP-514; see WO 2012/145493), cemiplimab (REGN-2810) (Regeneron; see WO 2015 /112800), JS001 (TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al., J. Hematol. Oncol. 10: 136 (2017)), BGB-A317 (Beigene; see WO 2015/35606 and US 2015/ 0079109), INCSHR1210 (SHR-1210; Jiangsu Hengrui Medicine; see WO 2015/085847; Si-Yang Liu et al., J. Hematol. Oncol. 10: 136 (2017)), TSR-042 (ANB011; Tesaro Biopharmaceutical ; see WO 2014/179664), GLS-010 (WBP3055; Wuxi/Harbin Gloria Pharmaceuticals; see 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, WO 2017/133540); BMS-936559 (formerly 12A4 or MDX-1105; see e.g. U.S. Patent 7943743 and WO 2013/173223), MPDL3280A (also known as RG7446, atezolizumab and TECENTRIQ; U.S. Patent 8217149; 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; see WO 2013/079174), STI-1014 (Sorrento; see WO 2013/181634), CX-072 (Cytomx; see WO 2016/149201), 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; see Gorelik et al., AACR: Abstract 4606 (Apr 2016)); urelumab, PF-05082566 , MEDI6469, TRX518, варлилумаб, СР-870893, BMS-986016, MGA271, лирилумаб, IPH2201, эмактузумаб, INCB024360, галунисертиб, улокуплумаб, BKT140, бавитуксимаб, СС-90002, бевацизумаб, MNRP1685A, иперилимумаб (YERVOY; патент США 6984720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; WO 2016/196237) and tremelimumab (formerly thicil imumab, CP-675,206; AstraZeneca; see, for example, WO 2000/037504 and Ribas, Update Cancer Ther. 2 (3): 133-39 (2007)).

In some 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, durvalamab, avellumab, STI -1014, CX-072, KN035, LY3300054, CK-301, urelumab, PF-05082566, MEDK469, TRX518, varlilumab, BMS-986016, ipilimumab, AGEN

- 27 042018

1884 and tremelimumab.

In some of these embodiments, the immune checkpoint inhibitor is selected from: urelumab, PF-05082566, MEDI6469, TRX518, varlilumab, Cp-870893, pembrolizumab (PD1), nivolumab (PD1), atezolizumab (formerly MPDL3280A) (PD-L1), avelumab (PD-L1), PDR001 (PD1), BMS986016, MGA271, lirilumab, IPH2201, emactuzumab, INCB024360, galunisertib, ulokuplumab, BKT140, bavituximab, CC16-90002P, bevacizumab, and MNRP1685A.

In some embodiments, the immune checkpoint inhibitor is selected from: nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab, and avelumab.

In some embodiments, the immune checkpoint inhibitor is selected from nivolumab and ipilimumab.

In some embodiments, the additional anti-cancer agent (chemotherapeutic agent) is a STING agonist. For example, a STING agonist may include cyclic dinucleotides such as cAMP, cGMP, and cGAMP, as well as modified cyclic dinucleotides that include one or more of the following modification features (2'-O/3'-O bond, phosphorothioate bond, adenine analog, and /or guanine, 2'-OH modification (eg -OCH3 or substitution, eg -F or N ₃ ) See, for example, WO 2014/189805.

In some embodiments, the additional chemotherapeutic agent is an alkylating agent. Alkylating agents are so named because of their ability to alkylate many nucleophilic functional groups under conditions found in cells, including, but not limited to, cancer cells. In another embodiment, the alkylating agent includes, but is not limited to, cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, and/or oxaliplatin. In one embodiment, alkylating agents may function by disrupting cell function by forming covalent bonds with amino, carboxyl, sulfhydryl, and phosphate groups on biologically important molecules, or they may act to alter the cell's DNA. In a further embodiment, the alkylating agent is synthetic, semi-synthetic, or a derivative.

In some embodiments, the additional chemotherapeutic agent is an antimetabolite. Antimetabolites masquerade as purines or pyrimidines, the building blocks of DNA, and generally prevent these substances from being incorporated into DNA during the S (cell cycle) phase, stopping normal development and division. Antimetabolites can also interfere with RNA synthesis. In one embodiment, the antimetabolite includes, but is not limited to, azathioprine and/or mercaptopurine. In a further embodiment, the antimetabolite is synthetic, semi-synthetic, or a derivative.

In some embodiments, the additional chemotherapeutic agent is a plant alkaloid and/or terpenoid. These alkaloids are derived from plants and block cell division, generally preventing microtubule function. In one embodiment, the plant alkaloid and/or terpenoid is a vinca alkaloid, podophyllotoxin and/or a taxane. Vinca alkaloids tend to bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules, typically during the M phase of the cell cycle. In one embodiment, the vinca alkaloid is derived, without limitation, from the Madagascar vinca, Catharanthus roseus (formerly known as Vinca rosea). In one embodiment, the vinca alkaloid includes, without limitation, vincristine, vinblastine, vinorelbine, and/or vindesine. In one embodiment, the taxane includes, but is not limited to, taxol, paclitaxel, and/or docetaxel. In another embodiment, the plant alkaloid or terpernoid is synthetic, semi-synthetic, or derived. In a further embodiment, podophyllotoxin is, without limitation, etoposide and/or teniposide. In one embodiment, the taxane is, without limitation, docetaxel and/or orthotaxel. In one embodiment, the cancer drug is a topoisomerase. Topoisomerases are important enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases disrupts both transcription and DNA replication, disrupting proper DNA supercoiling. In a further embodiment, the topoisomerase is, without limitation, a type I topoisomerase inhibitor or a type II topoisomerase inhibitor. In one embodiment, the type I topoisomerase inhibitor is, without limitation, camptothecin. In another embodiment, camptothecin is, without limitation, exatecan, irinotecan, lurtothecan, topotecan, BNP 1350, CKD 602, DB 67 (AR67), and/or ST 1481. In one embodiment, the type II topoisomerase inhibitor is, without limitation , epipodophyllotoxin. In another embodiment, epipodophyllotoxin is, without limitation, amsacrine, etoposide, etoposide phosphate, and/or teniposide. In another embodiment, the topoisomerase is synthetic, semi-synthetic, or derived, including those naturally occurring such as, but not limited to, epipodophyllotoxins, naturally occurring substances in the root of American Mayapple (Podophyllum peltatum).

In some embodiments, the additional chemotherapeutic agent is

- 28 042018 is a stilbenoid. In another embodiment, the stilbenoid includes, but is not limited to, resveratrol, piceatannol, pinosylvin, pterostilbene, alpha-viniferin, ampelopsin A, ampelopsin E, diptoindonesin C, diptoindonesin F, epsilon-vinferin, flexuosol A, gnetin D, chemsleyanol D, hopeeaphenol, trans-diptoindonesin B, astringin, piceid, and diptoindonesin A. In another embodiment, the stilbenoid is synthetic, semi-synthetic, or derived.

In some embodiments, the additional chemotherapeutic agent is a cytotoxic antibiotic. In one embodiment, the cytotoxic antibiotic is, without limitation, actinomycin, anthracenedione, anthracycline, thalidomide, dichloroacetic acid, nicotinic acid, 2-deoxyglucose, and/or chlofazimine. In one embodiment, the actinomycin is, without limitation, actinomycin D, bacitracin, colistin (polymyxin E), and/or polymyxin B. In another embodiment, the anthracenedione is, without limitation, mitoxantrone and/or pixantrone. In another embodiment, the anthracycline is, without limitation, bleomycin, doxorubicin (adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin, mitomycin, plicamycin, and/or valrubicin. In another embodiment, the cytotoxic antibiotic is synthetic, semi-synthetic, or a derivative.

In some embodiments, the additional chemotherapeutic agent is selected from endostatin, angiogenin, angiostatin, chemokines, angioarrestin, angiostatin (plasminogen fragment), basement membrane collagen-derived anti-angiogenic factors (tumstatin, canstatin, or arrestin), anti-angiogenic antithrombin III, signal transduction inhibitors, inhibitor cartilaginous origin (CDI), CD59 complement fragment, fibronectin fragment, gro-beta, heparinases, heparin hexasaccharide fragment, human chorionic gonadotropin (hCG), interferon alpha/beta/gamma, interferon-inducible protein (IP-10), interleukin-12 , kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMP), 2-methoxyestradiol, placental ribonuclease inhibitor, plasminogen activator inhibitor, platelet factor-4 (PF4), 16 kD prolactin fragment, proliferin-related protein (PRP), various retinoids, tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growth factor-beta (TGF-β), vasculostatin, vasostatin (calreticulin fragment), etc.

In some embodiments, the additional chemotherapeutic agent is selected from abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide, bleomycin, N,N-dimethylL-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro- 4'-deoxy-8'-norvin-kaleukoblastin, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine, dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea-taxanes, ifosfamide, liarozole, lonidamine, lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, takowsan, shepriest na, paclitaxel, prednimustine, procarbazine, RPR109881, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate and vinflunine.

In some embodiments, the additional 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, 5fluorouracil, leucovorin, methotrexate, gemcitabine, taxane, leucovorin, mitomycin C, tegafururacil, idarubicin, fludarabine, mitoxantrone, ifosfamide, and doxorubicin. Additional agents include mTOR (mammalian target of rapamycin) inhibitors including, but not limited to, rapamycin, everolimus, temsirolimus, and deforolimus.

In yet other embodiments, the additional chemotherapeutic agent may be selected from those described in US Pat. No. 7,927,613.

In yet another embodiment, the methods may further comprise administering one or both of: (i) one or more antifungal agents (e.g., selected from the group consisting of bifonazole, butoconazole, clotrimazole, econazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, сертаконазола, сульконазола, тиоконазола, альбаконазола, эфинаконазола, эпозиконазола, флуконазола, изавуконазола, итраконазола, позаконазола, пропиконазола, равусконазола, терконазола, вориконазола, абафунгина, аморолфина, бутенафина, нафтифина, тербинафина, анидулафунгина, каспофунгина, микафунгина, бензойной кислоты, циклопирокса, флуцитозина , 5-fluorocytosine, griseofulvin, haloprogin, tolnaflat, undecylenic acid, and Balsam of Peru), and (ii) one or more antibiotics (e.g., selected from the group consisting of amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin , geldanamycin, herbimycin, ri Faximin, loracarbef, ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cephalothin, cephalothin, cephalexi

- 29 042018 на, цефаклора, цефамандола, цефокситина, цефпрозила, цефуроксима, цефиксима, цефдинира, цефдиторена, цефоперазона, цефотаксима, цефподоксима, цефтазидима, цефтибутена, цефтизоксима, цефтриаксона, цефепима, цефтаролина фосамила, цефтобипрола, тейкопланина, ванкомицина, телаванцина, далбаванцина, оритаванцина, клиндамицина, линкомицина, даптомицина, азитромицина, кларитромицина, диритромицина, эритромицина, рокситромицина, тролеандомицина, телитромицина, спирамицина, азтреонама, фуразолидона, нитрофурантоина, линезолида, позизолида, радезолида, торезолида, амоксициллина, ампициллина, азлоциллина, карбенициллина, клоксациллина, диклоксациллина, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, penicillin G, temocillin, ticarcillin, amoxicillin, calvulanate, ampicillin, subbactam, piperacillin, tazobactam, ticarcillin, clavulanate, bacitracin, colistin, polymyxiproflon, enoxacin, gati флоксацина, гемифлоксацина, левофлоксацина, ломефлоксацина, моксифлоксацина, налидиксовой кислоты, норфлоксацина, офлоксацина, тровафлоксацина, грепафлоксацина, спарфлоксацина, темафлоксацина, мафенида, сульфацетамида, сульфадиазина, сульфадиазина серебра, сульфадиметоксина, сульфаметоксазола, сульфаниламида, сульфасалазина, сульфизоксазола, триметоприм-сульфаметоксазола, сульфонамидохризиодина, demeclocycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, dapreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, platensimypristin, mupirocin, dapremycin , thiamphenicol, tigecycline, tinidazole, trimethoprim and teixobactin).

In some embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting or administering the chemical compound (e.g., about one 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).

In other embodiments, the implementation of the second therapeutic agent or regimen is applied to the subject at about the same time as bringing into contact with the chemical compound or its introduction. For example, the second therapeutic agent or regimen and the chemical compound are administered to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical compound are administered to the subject simultaneously in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contact with or administration of the chemical compound (e.g., about one hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or after about 1 week, or after about 1 month).

Patient Selection

In some embodiments, the methods described herein further include the step of identifying a subject (eg, patient) in need of such treatment (eg, via biopsy, endoscopy, or other conventional method known in the art). In some embodiments, the implementation of the NLRP3 protein can serve as a biomarker for certain types of cancer.

In some embodiments, the chemicals, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (eg, patients resistant to checkpoint inhibitors).

In some embodiments, the implementation of the compounds of the present invention can be used in therapy. In some embodiments, the present invention provides a combination preparation consisting of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent(s), for simultaneous, separate, or sequential use in therapy.

In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, can be used as a drug. In some embodiments, the implementation of the compounds of the present invention can be used for the manufacture of drugs for the treatment of cancer.

In some embodiments, the compounds of the present invention can be used to make a medicament for modulating NLRP3 activity. In some embodiments, modulation includes agonizing NLRP3.

Manufacturing methods.

As the skilled artisan will appreciate, methods for synthesizing the compounds of the formulas provided 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 the methods described, for example, in US 2015/0056224, the contents of each of which are incorporated by reference. in full. Synthetic chemistries and protecting group methodologies (protection and deprotection) applicable to the synthesis of the compounds described herein are known in the art.

- 30 042018 and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and RGM. 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 their subsequent editions. The starting materials used in the preparation of the compounds of the invention are known, prepared by known methods, or commercially available. The skilled artisan will also appreciate that the conditions and reagents described herein may be replaced by alternative equivalents recognized in the art. For example, in many reactions, triethylamine can be replaced by other bases, such as non-nucleophilic bases (eg, diisopropylamine, 1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, or tetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical techniques that can be used to characterize the compounds described herein, including, for example, 1H NMR, heteronuclear NMR, mass spectrometry, liquid chromatography, and infrared spectroscopy. The above list is a subset of characterization methods available to the skilled artisan and is not intended to be limiting.

The following abbreviations have the meanings indicated:

ACN=acetonitrile,

AcOH=acetic acid,

CDCl ₃ = chloroform-d,

CD ₃ OD=methanol-d,

CH ₂ Cl ₂ = Dichloromethane,

CH ₃ ReO ₃ \u003d methyltrioxorhenium,

Cs ₂ CO ₃ \u003d cesium carbonate,

CuI=copper(I) iodide, d=doublet,

DCM=dichloromethane,

DIEA=N,N-diethylisopropylamine,

DMF=N,N-dimethylformamide,

DMSO=dimethyl sulfoxide,

ES=electrospray ionization,

Et ₂ O = diethyl ether,

EtOAc=ethyl acetate,

EtOH=ethanol, equiv.=equivalents, g=grams, h=hour(s),

HC1 = hydrogen chloride (usually in the form of a solution),

H ₂ O \u003d water,

H ₂ O ₂ \u003d hydrogen peroxide,

HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate,

HPLC=high performance liquid chromatography,

T2=iodine,

K ₂ CO ₃ \u003d potassium carbonate,

K ₂ HPO4 = potassium phosphate, dibasic,

K1=potassium iodide,

LC/MS=liquid chromatography/mass spectrometry,

LiBH4=lithium borohydride, m=multiplet, m/z=mass-to-charge ratio,

M=molar, m-CPBA=meta-chloroperoxybenzoic acid, mg=milligram(s),

MeOH=methanol,

MG c = megahertz, ml = milliliters (s), mmol = millimoles (s), MTO = methyltrioxorhenium, NaHCO ₃ = sodium hydrogen carbonate, Na ₂ CO ₃ = sodium carbonate, NaOH = sodium hydroxide,

- 31 042018

Na ₂ SO ₄ \u003d sodium sulfate,

NEt ₃ and TEA=trimethylamine,

NH ₄ OH or NH ₃ H ₂ O = ammonium hydroxide,

NH ₄ HCO ₃ \u003d rugpoKap6oHam ammonium, nm \u003d nanometer,

PdCl ₂ (PPh ₃ ) ₂ \u003d bis (triphenylphosphine) palladium (I) dichloride,

Pd (dppf) Cl ₂ \u003d 1.1 '-bis (diphenylphosphino) ferrocene,

Pd(dppf)Cl ₂ DCM=1,1'-bis(diphenylphosphino)ferrocene-dichloromethane complex,

Pd(OH) ₂ = palladium hydroxide,

PMB=p-methoxybenzyl,

POC1 ₃ =phosphorus oxychloride, ppm=ppm, Pt=platinum,

Pt/C=platinum on carbon, rt=room temperature, RT=retention time, s=singlet, t=triplet,

TFA=trifluoroacetic acid,

TLC = thin layer chromatography,

TosMIC=toluenesulfonyl methyl isocyanide,

TsCl=p-toluenesulfonyl chloride, °C=degrees Celsius, µmol=micromol(s).

The compounds of the present invention can be prepared in a number of ways 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, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof, which will be appreciated by experts in this field. Preferred methods include, but are not limited to, the methods described below.

Compounds of the present invention can be prepared using the reactions and procedures described in this section (eg, Schemes 1-11).

Compound 10 can be prepared using the synthetic sequence shown 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 . Treatment of intermediate 2 with an appropriately functionalized hydrazine (NH2-NHPG ¹ ) in the presence of an acid such as acetic acid provides intermediate 3 which can then be converted to intermediate 4 with a chlorinating agent such as POCl3. Addition of ammonia or an appropriately functionalized amine (NH2-PG ² ) to intermediate 4 provides intermediate 5. Deprotection of intermediate 5 can be accomplished in several ways known to the person skilled in the art. For example, when PG ¹ =PG ² =PMB, intermediate d 5 can be treated with a reagent such as TFA to give intermediate 6. Coupling between intermediate 6 and coupling reagent 7 under the action of a suitable catalyst provides intermediate 8 For example, this step can be carried out by treating intermediate 6 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 intermediate 8. Alternatively, this step can be carried out by treating intermediate 6 with a suitable heterocycle such as pyrazole in the presence of a copper catalyst such as copper(T) iodide and a ligand such as N,N '-dimethylethylenediamine to give intermediate 8. In the last step of Scheme 1, compound 10 can be prepared by treating intermediate 8 with an appropriately functionalized alkylating reagent (R2-X) where X is a leaving group such as a halide in the presence of a base such as potassium carbonate. Optionally, if R ³ contains a protecting group, it can be removed at this stage under suitable conditions. For example, if R ³ -M is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazole , the tetrahydropyran group can be removed by treatment with a reagent such as TFA.

- 32 042018

Scheme 1.

Alternatively, intermediate 6 can be first functionalized with an alkylating reagent R2-X to give compound 10a and then converted to compound 10 with a suitable binding partner ^R3 -M under the action of a catalyst as shown in Scheme 2.

Scheme 2.

An alternative synthesis of Intermediate 8 can be performed using the two-step sequence shown in Scheme 3. In the first step, Intermediate 5 (prepared as shown in Scheme 1) can be coupled with a suitable R ³ -M coupling reagent under the action of a suitable catalyst to give intermediate 11, which can then be deprotected with an acid such as TFA to give intermediate 8.

Scheme 3.

Analogues such as compounds 13a and 13b can be prepared according to the synthetic route illustrated in Scheme 4. Deprotection of 12 (prepared as shown in Scheme 1 or 2) can be performed using the appropriate conditions to give compound 13a . For example, if PG=Boc, this can be achieved by treatment with a reagent such as TFA. If R ³ contains a protecting group, this can also be removed at this stage. For example, if R ³ contains pyrazole protected with tetrahydropyran, treatment with a reagent such as TFA can remove this group. Compound 13a can then be converted to the desired end product by treatment with appropriate reagents. For example, 13a can be converted to an amide by treatment with an appropriately substituted carboxylic acid in the presence of a suitable coupling reaction reagent such as HATU and a base such as N,N-diisopropylethylamine. Alternatively, compound 13a can be converted to isoindolinone by treatment with a reagent such as methyl 2(bromomethyl)benzoate or an appropriately substituted analog thereof, in the presence of a base,

- 33 042018 such as 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 such as sodium triacetoxyborohydride. Alternatively, compound 13a can be converted to the sulfonamide by treatment with an appropriately substituted sulfonyl chloride in the presence of a base such as triethylamine. Alternatively, compound 13a can be converted to urea by treatment with an appropriately substituted isocyanate or carbamoyl chloride in the presence of a base such as triethylamine. Alternatively, compound 13a can be converted to the carbamate by treatment with an appropriately substituted chloroformate in the presence of a base such as triethylamine.

Scheme 4.

Analogues such as compounds 15a and 15b can be prepared according to the synthetic route illustrated in Scheme 5. Deprotection of intermediate 14 (prepared as shown in Scheme 1 or 2) can be carried out using suitable conditions to give compounds 15a. For example, if PG=TBS, this can be done by treatment with a reagent such as TBAF. Compound 15a can then be converted to compound 15b by treatment with appropriate reagents. For example, compound 15a can be converted to an aryl or heteroaryl ether by treatment with an appropriately substituted phenol in the presence of suitable reagents such as DIAD and triphenylphosphine. In the last step, if R ³ contains a protecting group, it can be removed using suitable conditions. For example, if R ³ contains pyrazole protected with tetrahydropyran, treatment with a reagent such as TFA can remove this group.

Scheme 5.

Compound 22 can be prepared using the synthetic sequence shown in Scheme 6. Intermediate 17 can be prepared by treating quinoline 16 with a suitable halogenating agent such as iodine in the presence of a base such as sodium hydroxide. Intermediate 17 can then be combined with an appropriately substituted alkyne 18 under the action of a suitable catalyst such as Pd(Ph ₃ ) ₄ to give the cyclized product 19. Further conversion to compound 21 can be carried out in a two-step sequence, first by treating the intermediate 19 with a suitable oxidizing agent such as m-CPBA to give oxide 20 which can be converted to compound 21 with a reagent such as tosyl chloride and an amine such as ammonia. Cross-coupling reaction between compound 21 and a suitable coupling partner under the action of a catalyst then gives compound 22.

Scheme 6.

- 34 042018

Analogues such as compound 29 can be prepared according to the synthetic route shown in Scheme 7. In Scheme 7, formation of an amide bond between intermediate 23 and acid 24 in the presence of a suitable coupling reagent such as HATU yields intermediate 25. compound 25 may undergo a cyclization reaction in the presence of suitable reagents such as C ₂ Cl6 and PPh ₃ to give intermediate 26. Further conversion to compound 28 may be carried out in a two-step sequence, first by treating intermediate 26 with a suitable oxidizing agent such as mCPBA to give oxide 27 which is then converted to compound 28 with a reagent such as tosyl chloride and an amine such as ammonia. Then cross-coupling reaction between compound 28 and a suitable coupling partner under the action of a catalyst gives compound 29.

Scheme 7.

R ² COOH J R ² ϊ 1 24 I Ϊ I stage 2 I G ⁴ ^R ² stage 3 p ^on -G Ar ⁰ - k / J) stage 1 I |JI P

Hal R ⁴ Ul-5l\4

Analogues such as Compound 33 can be prepared according to the synthetic route shown in Scheme 8. In Scheme 8, Intermediate 25 (prepared as shown in Scheme 7) can be converted to Intermediate 30 using a suitable reagent such as Lawesson's reagent, in the presence of a base such as pyridine. Further conversion to compound 32 can be done in a two-step sequence, first by treating compound 30 with a suitable oxidant such as m-CPBA to give oxide 31, which can be converted to compound 32 with a reagent such as tosyl chloride. and an amine such as ammonia. Cross-coupling reaction between compound 32 and a suitable coupling partner under the action of a catalyst then gives compound 33.

Scheme 8.

Analogues such as compound 40 can be prepared according to the synthetic methods shown in Scheme 9. In Scheme 9, compound 34 (prepared according to WO 2013/045400) can be protected with a suitable protecting group such as PMB to provide an intermediate compound 35. Intermediate 35 can then be converted to intermediate 36 using a chlorinating reagent such as POCl ₃ . Addition of ammonia or an appropriately functionalized amine (NH2-PG ² ) to intermediate 36 gives intermediate 37. Deprotection of intermediate 37 can be accomplished in several ways known to those skilled in the art. For example, if PG ¹ =PG ² =PMB, compound 5 can be treated with a reagent such as TFA to give intermediate 38. Compound 39 can be prepared by treating intermediate 38 with an appropriately functionalized alkylating reagent (R2-X), where X is a leaving group such as a halide in the presence of a base such as potassium carbonate. Coupling between compound 39 and a coupling reagent under the action of a suitable catalyst gives compound 40. Optionally, if R ³ contains a protecting group, it can be removed at this stage with

- 35 042018 using suitable conditions. For example, if R ³ -M is 1-(tetrahydro-2Hpyran-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.

Scheme 9.

Compound 52 can be prepared using the synthesis sequence shown in Scheme 10. In Scheme 10, treatment of quinoline 41, where the Hal ¹ group is a halide such as bromide, is substituted with amine 42, where R ^lb is H, a protecting group such as PMB or R ^la provides compound 43. Treatment of compound 43 with an iodinating reagent such as NIS gives compound 44 which can be coupled with an appropriately substituted alkyne 45 under the action of a suitable catalyst such as Pd(Ph ₃ ) ₂ Cl ₂ and CuI to give compound 46. Cyclization of compound 46 can be done with a base such as NaOH to give compound 47. Conversion to compound 48 can be done by treating compound 47 with a suitable oxidizing agent such as m-CPBA. Treatment of compound 48 with a reagent such as tosyl chloride and an amine such as ammonia gives compound 49. Coupling between compound 49 and the coupling reagent 50 under the action of a suitable catalyst gives compound 51. For example, this step can be carried out by treating compound 49 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)Cl ₂ to give compound 51. Alternatively, this step can be carried out by treating compound 49 with a suitable heterocycle such as pyrazole in the presence of

- 36 042018 in the presence of a copper catalyst such as copper(1) iodide and a ligand such as N,N'-dimethylethylenediamine to give compound 51. a reagent such as TFA.

Scheme 11.

Compound 61 can be prepared using the synthetic sequence shown in Scheme 11. In Scheme 11, treatment of quinoline 53, where the Hal ¹ group is a halide such as chloride, with an appropriately substituted hydrazine such as (4-methoxybenzyl)hydrazine provides the compound 54. Treatment of compound 54 with a suitable reagent such as PCl ₃ in a suitable solvent such as toluene gives compound 55. Conversion to compound 56 can be accomplished by treating compound 55 with a suitable oxidizing agent such as MTO. Compound 56 can then be converted to compound 57 with a suitable reagent such as POCl ₃ . Treatment of compound 57 with an amine such as ammonia provides compound 58. Deprotection of compound 58 can be carried out with an acid such as TFA to give compound 59. Coupling between compound 59 and a suitable coupling reagent with a suitable catalyst gives compound 60 For example, this step can be carried out by treating compound 59 with a suitable boronic acid ester such as 3-(tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole in the presence of a catalyst such as Pd(dppf)Cl ₂ to give compound 60. Compound 61 can be prepared by treating compound 60 with an appropriately functionalized alkylating reagent (R2-X) where X is a leaving group such as a halide in the presence of a base such as potassium carbonate. Optionally, if R ² or R ³ contains a protecting group, it can be removed at this stage using suitable conditions. For example, if R ³ -M is 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole , the tetrahydropyran group can be removed by treatment with a reagent such as TFA.

Examples

To further illustrate the foregoing, the following non-limiting illustrative synthesis schemes are included. Variations of these examples within the scope of the claims are within the purview of a person skilled in the art and are considered to fall within the scope of the invention as described and claimed herein. The reader will appreciate that a person skilled in the art provided by the present invention and skilled in the art will be able to make and use the invention without exhaustive examples.

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Example 1 Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propan-1-ol.

Step 1 Ethyl 2-(6-bromo-1H-indol-3-yl)-2-oxoacetate.

To a 150 ml round bottom flask was added 6-bromo-1H-indole (1.15 g, 5.89 mmol, 1.00 eq.) in Et ₂ O (30 ml). Ethyl 2-chloro-2-oxoacetate (922 mg, 6.78 mmol, 1.15 eq.) and pyridine (3 mL) were then added. The resulting solution was stirred at room temperature overnight. The reaction was then quenched by adding water. The resulting solution was extracted with ethyl acetate and the combined organic layers were concentrated in vacuo. The residue was purified on a silica gel column eluting 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 substances. LC-MS m/z 296.1 [M+H]+.

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 eq.) and [(4- methoxyphenyl)methyl]hydrazine (1.007 g, 6.62 mmol, 1.15 eq.) in ethanol (25 ml) and acetic acid (3 ml). The resulting solution was stirred overnight at 80°C. The reaction was then quenched by adding 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 with ethyl acetate/petroleum ether (4:1) to give 7bromo-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] ⁺ .

Stage 3. 7-bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[3,4-c]quinoline

A solution of 7-bromo-2-[(4-methoxyphenyl)-methyl]-2H,4H,5Hpyrazolo[3,4-c]quinolin-4-one (1.3 g, 3.38 mmol, 1.00 eq.) in dichloromethane (10 ml). DMF (0.5 ml) and POCl ₃ (1.031 g, 6.72 mmol, 2.00 eq.) were added to the solution. The resulting solution was stirred for 6 hours at 25°C. The reaction was then quenched by adding an aqueous solution of K2HPO4. 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[3,4c]quinoline (1 .17 g, 86%) as an off-white solid. LC-MS m/z 402.3 [M+H] ⁺ .

Step 4 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,6H,7H-pyrazolo[3,4-c]quinoline-4-amine

A solution of 7-bromo-4-chloro-2-[(4

- 38 042018 methoxyphenyl)methyl]-2H-pyrazolo[3,4-c]quinoline (180 mg, 0.45 mmol, 1.00 eq.) and ammonia (3 ml, 5.00 eq.) in dioxane (3 ml). The resulting solution was stirred overnight at 80°C. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane:CH ₃ OH (5:1) and the combined organic layers were concentrated in vacuo. The residue was purified on a silica gel column with dichloromethane/methanol (10:1) to give 7-bromo-2-[(4-methoxyphenyl)methyl]-2H,6H,7Hpyrazolo[3,4-c]quinoline-4-amine ( 140 mg, 81%) as a solid. LC-MS m/z 383.2 [M+H]+.

Step 5. 7-bromo-2H-pyrazolo[3,4-c]quinoline-4-amine.

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

Step 6 2-[3-(Benzyloxy)propyl]-7-bromo-2H-pyrazolo[3,4-c]quinoline-4-amine

A solution of 7-bromo-2H-pyrazolo[3,4c]quinoline-4-amine (688 mg, 2.62 mmol, 1.00 eq.) in DMF (8 ml) was added to a sealed 100 ml tube. Cs ₂ CO ₃ (1.029 g, 3.16 mmol, 1.20 eq.) and [(3-bromopropoxy)methyl]benzene (624.24 mg, 2.72 mmol, 1.10 eq.) were added to the solution. The resulting solution was stirred overnight at 25°C. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane:CH ₃ OH (5:1) and 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-2Hpyrazolo[3,4-c]quinoline-4-amine (500 mg, 46 %) as a dark red solid. LC-MS m/z 411.3 [M+H] ⁺ .

Step 7 2-[3-(Benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[5,4-c]quinoline-4-amine

A solution of 2-[3-(benzyloxy)-propyl]-7-bromo[1,3]oxazolo[5,4-c]quinoline-4-amine (500 mg, 1.21% mmol , 1.00 eq.), 3-(tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (472 mg, 2.43 mmol, 2.00 eq.) and Cs ₂ CO ₃ (1.193 mg , 3.00 eq.) in dioxane/water (10:1, 11 ml). Pd(dppf)Cl ₂ DCM (199.3 mg, 0.20 eq.) was added to the solution under a nitrogen atmosphere. The resulting solution was stirred overnight at 100°C. The reaction was then quenched by adding water. The resulting solution was extracted with dichloromethane:CH ₃ OH (5:1) 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 with dichloromethane/methanol (15:1) to give 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)[1,3]oxazolo[5,4- c]quinoline-4-amine (300 mg, 62%) as a solid. LC-MS m/z 399.2 [M+H] ⁺ .

Step 8 3-[4-Amino-7-(III-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]quinoline-4-amine (100 mg, 0.25 mmol, 1.00 eq.) in trifluoroacetic acid (5 ml). The resulting solution was stirred overnight at 70°C. The reaction was then quenched by adding water. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH4HCO3) and ACN (20.0% ACN to 55.0% in 9 min); detector, UV 254/210 nm. This provided 3-[4-amino-7-(1H-pyrazol-3-yl)-2H-n-pyrazolo[3,4-c]quinolin-2yl]propan-1-ol (11.6 mg, 15%) as a white solid. 1Н NMR (400 MHz, CD ₃ OD-d ₄ ) 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] ⁺ .

Example 2 Preparation of 2-(3-phenoxypropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4amine.

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Step 1. 7-bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

Cesium carbonate (25.1 mg, 0.077 mmol ) and then (3-bromopropoxy)benzene (15.2 mg, 0.071 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (20 ml), washed with H2O (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOH-CH ₂ C1 ₂ ) to give 7-bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinoline- 4-amines (17.1 mg, 67%). LC-MS m/z 397/399 [M+H]+.

Step 2 2-(3-phenoxypropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

A mixture of 7-bromo-2-(3-phenoxypropyl)-2H-pyrazolo[3,4-c]quinoline-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 H ₂ O (43 0 µl) at room temperature was purged with N2 for 5 min, 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 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H2O (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 16% B, 1656% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on the results of mass spectrometric measurements (MS). 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]quinoline-4-amine ( 3.6 mg, 22%). ¹ H NMR (500 MHz, DMSO-d ₆ ) 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, 2Н), 6.94-6.90 (m, 3H), 6.70 (d, J=2.1 Hz, 1H), 6.66-6.42 (m, 2Н), 4.62 (t, J=7.0 Hz, 2Н), 4.06-4.02 (m, 2Н), 2.41 (quin, J=6.4 Hz, 2Н). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 385.3 [M+H]+; RT: 1.39 min.

Examples 3 and 4 Preparation of 7-(1H-pyrazol-3-yl)-2-[3-(pyridin-2-yloxy)propyl]-2H-pyrazolo[3,4c]quinolin-4-amine and 1-{ 3-[4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]propyl}-1,2dihydropyridin-2-one.

Step 1 7-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

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 mixture was diluted with EtOAc (50 ml) and H ₂ O (50 ml). Layers

- 40 042018 was 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 Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give 7-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2Hpyrazolo[3, 4-c]quinoline-4-amine (214 mg, 77%) as a white solid, admixed with ~5% 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]+.

Step 2. 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)-2H-pyrazolo[3,4 -c]quinoline-4-amine.

A mixture of 7-bromo-2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-pyrazolo[3,4-c]-quinoline-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 refilled with N2, then 1,4-dioxane (4423 µl) and H2O (491 µl) were added. The resulting mixture was purged with N2 for 10 min, then [1,H-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.98 mg, 0.025 mmol) was added. The mixture was sparged with N ₂ for 1 min, then sealed and stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), washed with H ₂ O (50 ml) and saturated aqueous NaCl (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4c]quinoline-4-amine (242 mg, 97%) as a brown foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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=6.0 Hz, 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, 6Н); LC-MS m/z 507 [M+H] ⁺ .

Step 3. 3-(4-Amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4c]quinolin-2-yl) propan-1-ol.

To a solution of 2-(3-((tert-butyldimethylsilyl)oxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)-2H-pyrazolo[3,4- c]quinoline-4-amine (182 mg, 0.359 mmol) in THF (1796 μl) 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 product was purified by flash chromatography (24 g silica gel; linear gradient 0-100% EtOAcCH ₂ Cl ₂ then 0-10% MeOH-CH ₂ Cl ₂ ) to give 3-(4-amino-7-(1-(tetrahydro -2H-pyran-2-yl)-1Hpyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)-propan-1-ol (128 mg, 91%). S NMR (400 MHz, DMSOd ₆ ) 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] ⁺ .

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[3,4c]quinolin-2-yl)propane -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 diisopropyl azodicarboxylate (24.1 μl, 0.122 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo.

The crude product was dissolved in CH ₂ Cl ₂ (250 μl) and TFA (250 μl) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH2Cl2 and concentrated again. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 3% B, 3-43% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on the results of mass spectrometric measurements (MS). 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] quinoline-4-amine, TFA (28.5 mg, 56%) and 1-(3-(4-amino-7-(1 H-pyrazol-3-yl)-2H-pyrazolo[3,4-c] quinolin-2-yl)propyl)pyridin-2(1 H)-one, TFA (11.6 mg, 23%).

Characterization data for 7-(1H-pyrazol-3-yl)-2-(3-(pyridin-2-yloxy)propyl)-2Hpyrazolo[3,4-c]quinoline-4-amine, TFA: ¹ H NMR ( 500 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.86 (s, 1H), 8.15-8.07

- 41 042018 (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 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 386.3 [M+H]+; RT: 1.18 min.

Characteristic data for 1-(3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo-[3,4-c]quinolin-2yl)pronyl)pyridin-2(1H)-one , TFA: 78 (br s, 1H), 6.39 (d, J=9.1 Hz, 1H), 6.24 (t, J=62 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, 2.1x50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 386.3 [M+H]+; RT 1.03 min.

The compounds of Examples 5-9 were prepared according to synthetic procedures similar to those described in Example 3 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Example No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMSO-de) 5 ^N D N. //A, l—c n^X.— _h II N \—/ O N=Z ην / 403.1 1.55 δ 13.23 - 12.68 (m, 1H), 9.46 -9.07 (m, 2H), 9.01 (s, 1H), 8.11 (brs, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.89 (br d, 7=8.2 Hz, 1H), 7.79 (br s, 1H), 7.29 (q, 7=8.1 Hz, 1H), 6.78 6.72 (m, 4H), 4.70 (t, 7=6.9 Hz, 2H), 4.12 ( t, 7=6.0 Hz, 2H), 2.49 2.43 (m, 2H)

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6 S=^ yy N=< HN^y 403.3 1.67 δ 13.65 - 12.80 (m, 1H), 9.47-9.17 (m, 2H), 9.01 (s, 1H), 8.12 (brs, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.89 (brd, 7 =8.1 Hz, 1H), 7.80 (brs, 1H), 7.12 - 7.05 (m, 2H), 6.95 6.91 (m, 2H), 6.77 (d, 7=2.1 Hz, 1H), 4.70 (t, 7=6.9 Hz, 2H), 4.06 (t, 7=6.0 Hz, 2H), 2.45 (quin, 7=6.5 Hz, 2H) 7 H ₂ N A^ ^N F. £X/ ^N ^\ Ul AaV ⁰ \-A £ J HN \ 403.1 1.60 δ 13.77 - 12.92 (m, 1H), 9.86-9.17 (m, 2H), 9.05 (s, 1H), 8.16-8.12 (m, 1H), 8.10 (br d, 7=8.3 Hz, 1H), 7.90 ( br d, 7=7.7 Hz, 1H), 7.86 7.79 (m, 1H), 7.22-7.14 (m, 2H), 7.13-7.08 (m, 1H), 6.97-6.91 (m, 1H), 6.78 (s, 1H), 4.72 (brt, 7=6.7 Hz, 2H), 4.16 (brt, 7=5.6 Hz, 2H), 2.492.45 (m, 2H) 8 H ₂ N CH J___.N / ^CH3 AA ^{7 4} °A? £ J HN \ 398.9 1.74 δ 13.12-12.96 (m, 1H), 9.01 (s, 1H), 8.16-8.10 (m, 1H), 8.08 (brd, 7=8.0 Hz, 1H), 7.91 7.78 (m, 2H), 7.16-7.11 ( m, 1H), 6.78 (br s, 1H), 6.74 (br d, 7=7.2 Hz, 1H), 6.69 (s, 2H), 4.69 (brt, 7=6.6 Hz, 2H), 4.04 (brt, 7 =5.9Hz, 2H), 2.43(brt, 7=6.1Hz, 2H), 2.23(s, 3H) 9 H ₂ N )----N ^N L- ^Ν ν-\ IT A A;/- ⁷ AL/ £ J HN \ 386.1 0.89 δ 8.75 (s, 1H), 8.28 (d, 7=2.5 Hz, 1H), 8.16 (d, 7=3.9 Hz, 1H), 7.927.88 (m, 2H), 7.69 (br s, 1H), 7.62 (br d, 7=8.0 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.33 - 7.29 (m, 1H), 6.81 -6.68 (m, 3H), 4.63 (brt, 7=7.0 Hz, 2H) , 4.11 (t, 7=5.9 Hz, 2H), 2.46 2.41 (m, 2H)

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Example 10 Preparation of 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

Step 1. 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a 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 at room temperature (4-methoxyphenyl)methanamine (1.576 ml, 12.06 mmol) followed by N,K-diisopropylethylamine (3.15 ml, 18.09 mmol). The reaction mixture was stirred at 70°C for 18 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (500 ml), washed with H2O (2x250 ml) and saturated aqueous NaCl (250 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown oil. The crude product was purified by flash chromatography (40 g silica gel; linear gradient 0-100% EtOAc-hexanes) to give 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4-c]quinoline- 4-amines (2.880 g, 95%) as an off-white foam. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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]+.

Step 2 N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of pyrazole (97 mg, 1.43 mmol), 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[3,4c]quinoline-4-amine (600 mg, 1.19 mmol) , copper(I) iodide (11.35 mg, 0.060 mmol) and (1S,2S)-N1,N2dimethylcyclohexane-1,2-diamine (33.9 mg, 0.238 mmol) in toluene (2.5 ml) were added carbonate potassium (362 mg, 2.62 mmol). The reaction mixture was purged with N2 and stirred at 120° C. for 24 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (40 g silica gel; linear gradient 0-100% EtOAc-hexane) to give N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2Hpyrazolo[3 ,4-c]quinoline-4-amine (495 mg, 85%). LC-MS m/z 491.4 [M+H] ⁺ .

Step 3. 7-(1H-pyrazolo-1-ul)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of N,2-bis(4-methoxubenzyl)-7-(177-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine (501 mg, 1.02 mmol) in TFA (3934 µl, 51.1 mmol) anisole (1116 µl, 10.2 mmol) was added. 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 Et ₂ O and then filtered to give 7-(177-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, TFA salt (350 mg, 94%) . 1Н NMR (400 MHz, methanol-d ₄ ) 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] ⁺ .

Step 4 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of 1-bromo-2-ethoxyethane (9.17 mg, 0.060 mmol) and 7-(1H-pyrazol-1-yl)-2H-nirazolo[3,4c]quinoline-4-amine (15 mg, 0.060 mmol ) in DMF (0.3 ml) was added Cs ₂ CO ₃ (78 mg, 0.240 mmol). The reaction mixture was stirred at room temperature for 12 hours before being filtered. The crude product was purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 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 min hold at 6% B, 6-46% B for 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal precipitation.

- 44 042018 to obtain 2-(2-ethoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine (6.9 mg, 26%) . 1H NMR (500 MHz, DMSO-d ₆ ) 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 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 323.2 [M+H]+; RT: 1.03 min.

Compounds of examples 11-19 were obtained in accordance with the methods of synthesis described in example 10, from the appropriate starting materials. LC/MS method: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Example No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) eleven About NH ₂ % \^N 362.2 0.85 δ 8.72 (s, 1H), 8.53 (s, 1H), 7.99 (d, 7=8.5 Hz, 1H), 7.86 (s, 1H), 7.74 (s, 1H), 7.67 (br d, 7=7.3 Hz , 1H), 6.54 (br s, 1H), 4.57 (brt, 7=5.6 Hz, 2H), 3.71 (brt, 7=5.6 Hz, 2H), 3.17 (br d, 7=6.7 Hz, 2H), 2.15 (brt, 7=7.9Hz, 2H), 1.88 - 1.80 (m, 2H) 12 H ₃ c nh ₂ \ N--U _CH3 Xjj Vn 373.0 1.18 δ 8.47 (s, 1H), 8.40 (s, 1H), 7.93 (d, 7=8.4 Hz, 1H), 7.87 (d, 7=1.7 Hz, 1H), 7.74 (s, 1H), 7.65 (dd, 7=8.4, 1.8 Hz, 1H), 6.54 (s, 1H), 5.70 (s, 1H), 4.81 (brt, 7=5.9 Hz, 2H), 4.50 (brt, 7=5.9 Hz, 2H), 2.10 ( s, 3H), 1.88 (s, 3H) 13 NH ₂ / 0 1 X ^N - '- \=N 364.2 1.01 δ 8.71 (s, 1H), 8.47 (d, 7=2.1 Hz, 1H), 8.01 (d, 7=8.4 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.70 - 7.63 ( m, 1H), 6.54 (s, 1H), 4.57 (t, 7=6.4 Hz, 2H), 3.66 -3.46 (m, 4H), 2.91 (t, 7=6.4 Hz, 2H), 2.49 2.43 (m, 4H)

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14 nh _{2 n} ^A \ I \=N 342.0 1.08 5 8.83 (s, 1H), 8.56 (brd, 7=4.8 Hz, 1H), 8.48 (s, 1H), 8.04 (d, 7=8.4 Hz, 1H), 7.88 (d, 7=1.6 Hz, 1H) , 7.81 (t, 7=7.7 Hz, 1H), 7.74 (s, 1H), 7.67 (dd, 7=8.4, 1.9 Hz, 1H), 7.35 (dd, 7=7.3, 5.0 Hz, 1H), 7.26 ( d, 7=7.8 Hz, 1H), 6.54 (s, 1H), 5.79 (s, 2H) 15 T o f z y) 353.0 1.19 5 8.70 (s, 1H), 8.47 (br s, 1H), 8.02 (d, 7=8.4 Hz, 1H), 7.89 (brd, 7=1.8 Hz, 1H), 7.75 (s, 1H), 7.68 (br dd, 7=8.5, 2.0 Hz, 1H), 6.55 (s, 1H), 4.61 (brt, 7=5.2 Hz, 2H), 3.96 (brt, 7=5.1 Hz, 2H), 3.65 -3.51 (m, 2H ), 3.44 -3.35 (m, 2H), 3.20 (s, 3H) 16 o £ bl z- _z 4 u 348.2 0.95 5 8.70 (s, 1H), 8.54 (d, 7=2.1 Hz, 1H), 8.01 (d, 7=8.5 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.76 (s, 1H), 7.70 ( dd, 7=8.4, 1.7 Hz, 1H), 6.56 (s, 1H), 4.59-4.48 (m, 1H), 4.48 4.35 (m, 1H), 4.16-3.99 (m, 1H), 2.25 - 2.02 (m , 3H), 1.97-1.79 (m, 1H) 17 NH ₂ Z^b XXH ⁰ ijl N \ 1 V=N 335.2 1.24 5 8.68 (s, 1H), 8.50 (d, 7=1.5 Hz, 1H), 8.03 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.66 (br d , 7=7.0 Hz, 1H), 6.55 (s, 1H), 4.59 - 4.48 (m, 1H), 4.47 - 4.39 (m, 1H), 4.37-4.25 (m, 1H), 3.78 (br d, 7= 7.3 Hz, 2H), 2.01 (brdd, 7=12.1, 6.0 Hz, 1H), 1.891.75 (m, 2H), 1.72-1.59 (m, 1H) 18 NH ₂ aX ⁿ ^° X/J \=N 349.2 1.16 5 8.67 (s, 1H), 8.53 (d, 7=1.8 Hz, 1H), 8.02 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.67 (dd, 7=8.4, 1.7 Hz, 1H), 6.55 (s, 1H), 4.58-4.33 (m, 2H), 3.84 (brt,7=11.7 Hz, 2H), 3.31 (brt, 7=9.3 Hz, 1H), 1.81 (brd,7=11.0 Hz, 1H), 1.64 (brd,7=12.5 Hz, 1H), 1.53 - 1.38 (m, 3H), 1.34-1.18 (m, 1H) 19 N _n 1 °\\ _k1 ^sn ₃ fW JGJ \^N 336.3 1.03 5 8.68 (s, 1H), 8.50 (d, 7=2.3 Hz, 1H), 8.16 (brs, 1H), 8.04 (d, 7=8.4 Hz, 1H), 7.88 (d, 7=2.0 Hz, 1H) , 7.75 (s, 1H), 7.68 (dd, 7=8.4, 2.1Hz, 1H), 6.54 (s, 1H), 5.13 (s, 2H), 3.17 (m, 2H), 1.09 (t, 7=7.2 Hz, 3H)

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Example 20 Preparation of 2-[2-(morpholin-4-yl)ethyl]-7-(III-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline4-amine.

Step 1. 7-(1-(Tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

7-Bromo-2H-pyrazolo[3,4-c]quinoline-4-amine mixture, 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 tribasic potassium phosphate (5.05 g, 23.8 mmol) were evacuated and again filled with N2, then it was mixed with dioxane (33.0 ml) and H2O (6.60 ml). The resulting suspension was bubbled with N2 for 15 min, 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). The reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (400 ml) and H2O (400 ml). The layers were separated and the aqueous layer was extracted with EtOAc (2x200 ml). The combined organic layers were washed with saturated aqueous NaCl (400 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was mixed with CH ₂ Cl ₂ (10 ml), filtered and washed with CH ₂ Cl ₂ (3x10 ml) to give 7-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl )-2H-pyrazolo[3,4c]quinoline-4-amine (1.865 g, 70%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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]+.

Step 2 2-[2-(morpholin-4-yl)ethyl]-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo-[3,4-c]quinoline-4-amine (16.3 mg, 0.049 mmol) in DMF (162 μl) 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 hours, the Reaction mixture was diluted with H ₂ O (2 ml) and was extracted with EtOAc (3x2 ml). The combined organic layers were concentrated.

The crude product was mixed with CH ₂ Cl ₂ (200 μl) and TFA (200 μl) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 6% B, 6-46% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS signals. 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]quinoline-4-amine (10.8 mg, 59%). 1Н 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 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 363.9 [M+H]+; RT: 0.84 min.

The compounds of Examples 21-28 were prepared according to synthetic procedures similar to those described in Example 20 from the appropriate starting materials. In example 27, the reaction mixture was stirred at 50° C. for 4 hours. For reactions in which two regioisomeric peaks were observed by HPLC, the product was usually the main peak and was the more polar of the two peaks observed under the HPLC conditions used. Analytical LC/MS conditions: column: Waters

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XBridge 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 21 CO co I T O, Z Z o ¹ νθ m Ζ 322.2 0.61 5 9.00 (s, 1H), 8.14-8.08 (m, 2H), 7.90 (d, 7=8.3 Hz, 1H), 7.79 (s, 1H), 6.77 (d, 7=2.1 Hz, 1H), 4.94 ( brt, 7=5.9 Hz, 2H), 3.75 -3.69 (m, 2H), 2.87 (s, 6H 22 η ₂ ν ¹ N' ^CH 3 £ J ^Η3 θ HN ) 336.1 0.86 5 13.27-12.87 (m, 1H), 9.98 -9.19(m, 2H), 8.99 (s, 1H), 8.15-8.07 (m, 2H), 7.91 (br d, 7=7.7 Hz, 1H), 7.83 ( brs, 1H), 6.79 (d, 7=1.7 Hz, 1H), 4.61 (t, 7=6.6 Hz, 2H), 3.173.12 (m, 2H), 2.79 (s, 6H), 2.39 - 2.30 (m , 2H) 23 H ₂ N o AsT N - \ ? G ^H HN 1 398.1 1.21 5 10.11 (s, 1H), 8.97 (s, 1H), 8.12 (d, 7=8.3 Hz, 1H), 8.08 (brs, 1H), 7.88 (brd,7=8.5 Hz, 1H), 7.52 (br d , 7=8.3 Hz, 2H), 7.30 - 7.24 (m, 3H), 7.07 - 7.00 (m, 1H), 6.78 (s, 1H), 4.82 (brt,7=6.5 Hz, 2H), 3.13 (brt, 7=6.3Hz, 2H) 24 I l-z All i <Qry ^z IL? ZI (about c? 336.4 0.80 5 8.68 (s, 1H), 8.27 (brt, 7=5.1 Hz, 1H), 7.96 (brd, 7=8.0 Hz, 1H), 7.90 (s, 1H), 7.76 - 7.59 (m, 2H), 6.89 6.79 (m, 2H), 6.74 (s, 1H), 5.13 (s, 2H), 3.18-3.11 (m, 2H), 1.06 (t, 7=7.3 Hz, 3H) 25 NH ₂ ZZ mDL hn' J 342.1 1.02 5 9.03 (s, 1H), 8.54 (brd, 7=4.4 Hz, 1H), 8.10 (d, 7=8.3 Hz, 1H), 8.05 (br d, 7=0.8 Hz, 1H), 7.86 - 7.73 (m , 3H), 7.39 -7.31 (m, 2H), 6.78 (s, 1H), 5.85 (s, 2H) 26 nh ₂ n^ 7 r n—< nULJ b hn Ύ 370.2 0.95 5 8.71 (s, 1H), 8.43 (s, 1H), 8.37 (brd, 7=3.6 Hz, 1H), 7.93 (d, 7=8.3 Hz, 1H), 7.88 (s, 1H), 7.70 - 7.65 ( m, 2H), 7.63 (brd,7=8.3 Hz, 1H), 7.31 (dd, 7=7.4, 5.0 Hz, 1H), 6.80 - 6.66 (m, 3H), 4.45 (br t, 7=6.9 Hz, 2H), 2.66-2.61 (m, 2H), 2.30 - 2.22 (m, 2H) 27 ABOUT CN ) ( z T 378.0 0.92 5 13.41 - 12.76 (m, 1H), 8.73 (s, 1H), 7.96 - 7.87 (m, 2H), 7.81 -7.56 (m, 2H), 7.02 6.80 (m, 2H), 6.74 (br s, 1H) , 4.47 (brt, 7=6.7 Hz, 2H), 3.59 - 3.53 (m, 4H), 2.37 2.32 (m, 4H), 2.31 (brt, 7=7.0 Hz, 2H), 2.14 -2.07 (m, 2H) 28 nh ₂ Pa V ^NH nJU ⁰ hnj U 385.0 0.87 5 11.01 (brs, 1H), 8.76 (s, 1H), 8.37 (brd,7=1.4 Hz, 1H), 8.04 - 7.96 (m, 2H), 7.91 (brs, 1H), 7.83 -7.78 (m, 1H ), 7.76 - 7.60 (m, 2H), 7.18 - 7.11 (m, 1H), 7.00 - 6.82 (m, 2H), 6.75 (br s, 1H), 5.49 (br s, 2H)

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Example 29.

N-ethylacetamide.

Obtaining N-[2-[4-aMUHO-7-(1 H-pyrazol-3 -yl)-2H-pyrazolo [3,4-c]quinolin-2-yl]ethyl] -

Step 1. 7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a 250 ml round bottom flask was added 7-bromo-2H-pyrazolo[3,4-c]quinoline-4-amine (2 g, 7.60 mmol, 1 eq.), DMF (70 ml, 957.67 mmol) , Cs ₂ CO ₃ (5.0 g, 15.20 mmol, 2 eq.) and 1,2-dibromoethane (2.1 g, 11.40 mmol, 1.5 eq.). The resulting solution was stirred for 5 h at room temperature and then diluted with EtOAc (350 ml). The resulting mixture was washed with H2O (2x100 ml) and brine (2x100 ml). The mixture was then concentrated and the residue was purified on a silica gel column using ethyl acetate/petroleum ether (0-70%) to give 7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinoline-4 -amine (1.5 g, 53%) as a solid. LC-MS m/z [M+H]+=368.9.

Step 2 7-bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinoline-4-amine.

7-bromo-2-(2-bromoethyl)-2H-pyrazolo[3,4-c]quinoline-4-amine (500 mg, 1.35 mmol, 1 eq.), ACN ( 10 ml, 0.24 mmol), K2CO3 (373.5 mg, 2.70 mmol, 2 eq.), KI (22.4 mg, 0.14 mmol, 0.1 eq.) and ethanamine (609.2 mg, 13.51 mmol, 10 eq.). The resulting solution was stirred for 16 hours at 65°C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column using dichloromethane/methanol (0-10%) to give 7bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinoline-4-amine (250 mg, 55%) as a solid. LC-MS m/z [M+H] ⁺ =334.1.

Step 3 N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-N-ethylacetamide.

To a 25 ml three-necked round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added 7-bromo-2-[2-(ethylamino)ethyl]-2H-pyrazolo[3,4-c]quinoline-4-amine (250 mg , 0.75 mmol, 1 eq.), DCM (10 ml, 157.30 mmol), TEA (227.1 mg, 2.24 mmol, 3 eq.) and Ac ₂ O (91.6 mg, 0. 90 mmol, 1.2 eq.). The resulting solution was stirred for 5 hours at room temperature. 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)-Nethylacetamide (200 mg, 71%) as a solid. LC-MS m/z [M+H] ⁺ = 376.1.

Step 4 N-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]-N-ethylacetamide.

N-(2-[4-Amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2yl]ethyl)-N-ethylacetamide (200 mg, 0.53 mmol, 1 eq.), Na ₂ CO ₃ (112.7 mg, 1.06 mmol, 2 eq.), 3(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (206.3 mg , 1.06 mmol, 2 eq.), Pd(PPh ₃ ) ₄ (61.4 mg, 0.05 mmol, 0.1 eq.) in dioxane (5 ml, 0.06 mmol) and H ₂ O ( 1.25 ml, 620.08 mmol). The resulting solution was stirred for 16 hours at 80° C. in an oil bath. 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 preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD, column 19x250 mm, 10 µm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 13 to 40% B over 7 min; 254/210 nm; RT: 6.55 min. This provided 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-d ₆ , 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 methods: column: Kinetex EVO 3.0x50 mm, particles

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2.6 µm; mobile phase A: water with 0.03% NH ₃ H ₂ O; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold for 0.60 min at 95% B; flow rate: 1.2 ml/min. m/z [M+H]+=336.3. LC RT: 1.030 min.

Example 30 Preparation of 2-(2-{hexahydro-1H-furo[3,4-c]pyrrol-5-yl}ethyl)-7-(1H-pyrazol-3-yl)-2Hpyrazolo[3,4-c ]quinoline-4-amine.

HN-N

Step 1. 7-bromo-2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-2H-pyrazolo[3,4-c]quinoline-4amine.

7-bromo-2-(2-bromoethyl)-2H-pyrazolo-[3,4-c]quinoline-4amine (400 mg, 1.08 mmol, 1 eq.), K ₂ CO ₃ (298.8 mg, 2.16 mmol, 2 eq.), KI (17.9 mg, 0.11 mmol, 0.1 eq.) and hexahydro-1H-furo[3,4-c]pyrrole ( 611.6 mg, 5.40 mmol, 5 eq) in ACN (10 mg, 0.24 mmol, 0.225 eq). The resulting solution was stirred for 16 hours at 65°C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column using 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]quinoline-4-amine (120 mg, 28%) as a solid. LC-MS: (ES, m/z): [M+H] ⁺ =402.1.

Step 2. 2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3.4c] quinoline-4-amine.

7-bromo-2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)2H-pyrazolo[3,4-c]quinoline-4 -amine (120 mg, 0.30 mmol, 1 eq.), Na ₂ CO ₃ (63.2 mg, 0.60 mmol, 2 eq.), 3 (tetramethyl-1,3,2-dioxaborolane-2- yl)-1H-pyrazole (115.8 mg, 0.60 mmol, 2 eq.), Pd(PPh ₃ ) ₄ (34.5 mg, 0.03 mmol, 0.1 eq.) in dioxane (4 ml ) and H ₂ O (1 ml). The resulting solution was stirred for 16 h at 80°C. The resulting mixture was cooled to room temperature and concentrated. The residue was purified on a silica gel column using dichloromethane/methanol (0-10%). The crude product was again purified by preparative HPLC using the following conditions: column: XBridge Shield RP18 OBD, column 19x250 mm, 10 µm; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 15 to 40% B over 7.5 minutes; 210/254 nm; RT: 6.90 min. This provided 2-(2-[hexahydro-1H-furo[3,4-c]pyrrol-5-yl]ethyl)-7-(1H-pyrazol-3-yl)-2Hpyrazolo[3,4- c]quinoline-4-amine (27.9 mg, 24%) as a solid. ¹ H-NMR: (300 MHz, DMSO-d ₆ , 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 Methods: Column: Kinetex EVO 3.0x50 mm, particles 2.6 µm; mobile phase A: water with 0.03% NH3H2O; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.60 min at 95% B; flow rate: 1.2 ml/min. m/z [M+H] ⁺ =390.2. LC RT: 1.030 min.

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Example 31 Preparation of N-{2-[4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}5-fluoropyridin-2- carboxamide.

Step 1: tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-carbamate.

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 room temperature for 20 hours. The reaction mixture 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 Na ₂ SO ₄ and filtered.

Celite was added and the mixture concentrated in vacuo. This dry product was loaded onto a column and purified by flash chromatography (80 g silica gel with 25 g solid-load cartridge; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give t-butyl (2-(4-amino -7-bromo-2H-pyrazolo[3,4c]quinolin-2-yl)ethyl)carbamate (2.06 g, 64%) as a white solid. ¹ H NMR (400 MHz,

DMSO-d ₆ ) 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]+.

Step 2. tert-butyl 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)-III-pyrazole (1.037 g, 3.73 mmol) and cesium carbonate (2.430 g, 7.46 mmol) was evacuated and refilled with N ₂ , then 1,4-dioxane (22.37 ml) and H ₂ O (2.486 ml) were added. The resulting mixture was sparged with N ₂ for 15 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.091 g, 0.124 mmol) was added. The mixture was sparged with N2 for 1 min, then stirred at 100°C for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (300 ml), washed with H2O (150 ml) and saturated aqueous NaCl (150 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (80 g silica gel; linear gradient 010% MeOH-CH ₂ Cl ₂ ) to give tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2)- yl)-1H-pyrazol5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (1.2 g, quant.) as a yellow solid. 1H NMR (400 MHz, DMSO-d ₆ ) 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, 2Н), 4.07-4.01 (m, 1H), 3.61-3.54 (m, 1H), 3.50 (q , J=6.0 Hz, 2Н), 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] ⁺ .

Step 3 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA.

To a solution of tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[3,4-c]quinoline-2 -yl)ethyl)carbamate (1.2 g, 2.5 mmol) in CH2Cl2 (6.17 ml) TFA (6.17 ml) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (75 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x10 ml) to give 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4 α-amine, 2 TFA (1.121 g, 87%) as an off-white solid. 1Н NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

Step 4 N-{2-[4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-5fluoropyridine-2-carboxamide.

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (40 mg,

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0.077 mmol) and 5-fluoropicolic acid (10.8 mg, 0.077 mmol) in DMF (384 µl) N,N-diisopropylethylamine (53.5 µl, 0.307 mmol) was added at room temperature followed by HATU (29.2 mg , 0.077 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 μm; 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 min hold at 2% B, 2-42% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on 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, 2 TFA (15.8 mg, 31%). ¹ H 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, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 417.3 [M+H]+; RT: 1.13 min.

Alternative procedure for the preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo-[3,4c]quinolin-2-yl]ethyl}-5-fluoropyridine-2-carboxamide .

To a solution of 5-fluoropicolic acid (29.8 mg, 0.211 mmol) in DMF (479 µl) at room temperature was added N,N-diisopropylethylamine (66.8 µl, 0.384 mmol) followed by HATU (72.9 mg, 0.192 mmol ). This solution was stirred at room temperature for 5 min, then added dropwise to a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4 -amine, 2 TFA (100 mg, 0.192 mmol) and N,N-diisopropylethylamine (100 μl, 0.575 mmol) in DMF (479 μl). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture 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 10% aq. LiCl (2x50 ml) and saturated aqueous NaCl (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was taken up in MeOH-CH ₂ Cl ₂ , celite was added and the mixture was concentrated in vacuo. This product was loaded onto the column dry and purified by flash chromatography (24 g RediSep Gold silica gel with 5 g solid load cartridge; linear gradient 0-20% MeOH-CH ₂ Cl ₂ ) to give 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. 1Н 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] ⁺ .

The compounds of Examples 32-101 were prepared according to synthetic procedures similar to those described in Example 31 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMSO-d ₆ )

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32 ° κ-χ ^ΝΗ Λ I η ₂ ν / Χ-Ά och ₃ Ο ν=(~^ ΗΝ^ 442.3 0.98 5 8.54 (s, 1H), 8.12 (br t, 7=5.6 Hz, 1H), 7.91 -7.87 (m, 2H), 7.70 (br s, 1H), 7.64 (brd, 7=7.7 Hz, 1H), 7.06 (d, 7=8.3 Hz, 2H), 6.80 (br s, 2H), 6.75 -6.71 (m, 3H), 4.49 (brt, 7=5.8 Hz, 2H), 3.65 (s, 3H), 3.63 - 3.59 (m, 2H), 3.30 (s, 2H) 33 CO Τ Ο /^ο ΙΖ ζ_ ^ζ ϋΐ ^χ 1GA = _ζ ² τ 336.1 0.73 5 8.63 (s, 1H), 7.96 - 7.92 (m, 2H), 7.89 (s, 1H), 7.67 (s, 1H), 7.64 (d, 7=8.0 Hz, 1H), 6.71 (s, 1H), 4.49 (t, 7=6.0 Hz, 2H), 3.65 - 3.58 (m, 2H), 1.81 (s, 3H) 34 ^N L Ν ₄ Η SNz Ν^Χ^-Ν / 4 W USN ₃ /=/ ⁰ W Ν=( ΗΝ^ 364.2 0.86 5 8.61 (s, 1H), 7.94 - 7.85 (m, 3H), 7.81 -7.54 (m, 1H), 6.90 -6.64 (m, 2H), 4.48 (brt, 7=5.8 Hz, 2H), 3.60-3.55 (m, 2H), 2.30 (quin, 7=6.8 Hz, 1H), 0.95 (d, 7=6.9 Hz, 6H) 35 Η ₂ N k^ ^N _4| _ Η )==2 DON Ο ⁰ ΗΝ 3 352.2 0.69 5 8.67 (s, 1H), 8.02 (brt, 7=5.6 Hz, 1H), 7.93 (brd, 7=7.4 Hz, 1H), 7.89 (brs, 1H), 7.79 - 7.57 (m, 2H), 6.86 - 6.76 (m, 2H), 6.73 (s, 1H), 5.54 (brt,7=5.5 Hz, 1H), 4.53 (brt,7=5.9 Hz, 2H), 3.80 (br d, 7=5.2 Hz, 2H) , 3.71-3.65 (m, 2H) 36 I ο GT γ ^ζ Υ> ΖΙ 0^2 ο 398.2 0.98 5 8.70 (s, 1H), 8.67 (brt, 7=5.9 Hz, 1H), 7.90 (d, 7=8.5 Hz, 1H), 7.88 (s, 1H), 7.79 (d, 7=7.4 Hz, 2H) , 7.69 (br s, 1H), 7.60 (brd,7=8.0 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.47 -7.41 (m, 2H), 6.73 (s, 1H), 6.82 - 6.69 ( m, 2H), 4.63 (br t, 7=5.9 Hz, 2H), 3.82 (q, 7=5 .7 Hz, 2H) 37 η ₂ ν Ν^Υ_ _Ζ ^Ν ^—Ν /Г Ν 22 ⁰ Ν==Ζ ΗΝ\ 399.3 0.95 5 13.71 - 13.34 (m, 1H), 9.91 -9.67 (m, 1H), 9.33 -9.12 (m, 1H), 9.02 (s, 1H), 8.97 (br s, 1H), 8.71 (brd,7=3.6 Hz, 2H), 8.13 (s, 1H), 8.10 (brd, 7=8.5 Hz, 1H), 7.97 - 7.88 (m, 1H), 7.82 (s, 1H), 7.68 (br d, 7=4.1 Hz, 2H), 6.78(s, 1H), 4.74-4.69(m, 2H), 3.91-3.84(m, 2H)

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38 h ₂ n ⁰ N^/ HN J 399.2 0.95 5 8.94 (s, 1H), 8.88 (brt, 7=4.7 Hz, 1H), 8.72 (s, 1H), 8.69 (br d, 7=4.7 Hz, 1H), 8.13 (brd, 7=8.0 Hz, 1H ), 7.92 - 7.87 (m, 2H), 7.69 (br s, 1H), 7.60 (brd,7=8.3 Hz, 1H), 7.48 (dd, 7=7.3, 4.8 Hz, 1H), 6.80 - 6.70 (m , 3H), 4.63 (brt, 7=5.5 Hz, 2H), 3.873.81 (m, 2H) 39 H ₂ N ⁰ N=Z HN J 399.3 1.06 5 13.54 - 13.37 (m, 1H), 9.89 -9.76 (m, 1H), 9.24-9.13 (m, 1H), 9.11 (brt,7=5.6Hz, 1H), 8.98 (s, 1H), 8.62 (brd , 7=4.4 Hz, 1H), 8.12 (brs, 1H), 8.09 (brd,7=8.5 Hz, 1H), 8.01 -7.95 (m, 2H), 7.88 (brd,7=8.0 Hz, 1H), 7.82 (br s, 1H), 7.60 (brt, 7=4.5 Hz, 1H), 6.78 (s, 1H), 4.74 (brt, 7=5.2 Hz, 2H), 3.96-3.90 (m, 2H) 40 X^xOSCH3 ⁿ ίι T H ₂ NN . _N /\/ N ° yy N=< HN^ 428.1 1.16 5 8.70 (s, 1H), 8.53 (t, 7=5.2 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.78 (d, 7=8.5 Hz, 2H), 7.71 7.67 (m, 1H), 7.62 (br d, 7=9.1 Hz, 1H), 6.97 (d, 7=8.5 Hz, 2H), 6.97 - 6.80 (m, 2H), 6.73 (s, 1H), 4.61 (brt, 7=6.1 Hz, 2H ), 3.83 - 3.78 (m, 5H) 41 /<uCH ₃ ^H2 V'n^W ° O N =< HN^ 412.2 1.20 5 8.71 - 8.67 (m, 1H), 8.59 (br t, 7=4.7 Hz, 1H), 7.92 - 7.87 (m, 2H), 7.73 - 7.67 (m, 3H), 7.60 (brd, 7=8.0 Hz, 1H), 7.24 (br d, 7=7.4 Hz, 2H), 6.79 - 6.74 (m, 2H), 6.73 (s, 1H), 4.62 (brt, 7=5.4 Hz, 2H), 3.83 -3.77 (m, 2H), 2.33(s, 3H) 42 ⁿ GU ⁰ yy N =/ HNy^ 416.1 1.17 5 8.99 (s, 1H), 8.73 - 8.67 (m, 1H), 8.17-8.05 (m, 2H), 7.92 -7.79 (m, 4H), 7.27 (brt, 7=8.8 Hz, 2H), 6.80 - 6.75 (m, 1H), 4.72 - 4.67 (m, 2H), 3.85 (q, 7=5.4 Hz, 2H) 43 CH ₃ yy y N=/ 419.2 1.06 5 8.70 - 8.66 (m, 1H), 8.62 (br t, 7=5.5 Hz, 1H), 8.07 (s, 1H), 7.91 (brd, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.72 - 7.65 (m, 1H), 7.64 - 7.58 (m, 1H), 6.73 (br s, 3H), 4.62 (brt, 7=6.2 Hz, 2H), 3.83 (q, 7=6.3 Hz,

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2H), 2.67(s, 3H) 44 h ₂ n _n hn=\ o N=Z HN^ 389.3 0.75 5 13.16-12.98 (m, 1H), 8.99 - 8.92 (m, 1H), 8.63 - 8.57 (m, 2H), 8.48 (s, 1H), 8.188.05 (m, 2H), 7.94 - 7.78 (m, 2H), 6.78 (br s, 1H), 4.68 (br t, J=5.5 Hz, 2H), 3.87 -3.82 (m, 2H) 45 ch ₃ H ₂ N μ H /=\ ^z ^N 'N^N O N=Z HN^y 416.3 0.84 5 8.67 (s, 1H), 8.25 (brt, 7=5.9 Hz, 1H), 7.91 (brd, 7=8.3 Hz, 1H), 7.89 (s, 1H), 7.69 (brs, 1H), 7.61 (brd, 7=8.3 Hz, 1H), 6.82 - 6.74 (m, 2H), 6.73 (d, 7=1.4 Hz, 1H), 6.38 (s, 1H), 4.59 (brt, 7=6.2 Hz, 2H), 3.81 - 3.76 (m, 2H), 3.74 (s, 3H), 2.24 (s, 3H) 46 H ₃ C H ₂ N n ^h F\\ ² kA^N Y _o XcH ₃ nH & y) N=/ HN^ 417.4 0.32 5 8.69 (s, 1H), 8.47 (brt, 7=5.6 Hz, 1H), 7.92 (brd, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.75 - 7.64 (m, 1H), 7.64 7.58 (m, 1H), 6.73 (br s, 3H), 4.58 (brt,7=6.1 Hz, 2H), 3.77 (q,7=5.6 Hz, 2H), 2.39 (s, 3H), 2.28 (s, 3H ) 47 ^ν ΓΑ 0 o N=Z ^HN ^ 406.2 0.96 5 8.88 (s, 1H), 8.08 (brd, 7=8.3 Hz, 2H), 7.97 (brt, 7=5.6 Hz, 1H), 7.89 - 7.83 (m, 1H), 7.83 - 7.77 (m, 1H), 6.78 (s, 1H), 4.55 (brt, 7=5.8 Hz, 2H), 3.82 - 3.77 (m, 2H), 3.62 (q, 7=5.4 Hz, 2H), 3.28 3.21 (m, 2H), 2.34 - 2.26 (m, 1H), 1.55 - 1.48 (m, 4H) 48 fv ^ ^CHS o N=Z HN^ 350.2 0.97 5 13.55 - 12.85 (m, 1H), 9.59 -9.01(m, 2H), 8.92 (s, 1H), 8.16-8.08 (m, 2H), 7.90 (br d,7=8.1 Hz, 1H), 7.86 ( brt, 7=5.4 Hz, 1H), 7.83 - 7.77 (m, 1H), 6.77 (d, 7=1.8 Hz, 1H), 4.57 (t, 7=6.0 Hz, 2H), 3.65 (q, 7=5.7 Hz, 2H), 2.07 (q, 7=7.5 Hz, 2H), 0.98 (t, 7=7.6 Hz, 3H)

- 55 042018

49 CH ₃ n Τι Ί Aw ⁰ Ν=< ΗΝ^ 413.0 1.27 δ 13.35 - 12.51 (m, 1H), 8.83 - 8.76 (m, 1H), 8.69 (s, 1H), 7.92 - 7.88 (m, 2H), 7.86 7.80 (m, 2H), 7.76 - 7.54 (m, 2H ), 7.45-7.41 (m, 1H), 6.71 (d, 7=1.3 Hz, 1H), 6.68 -6.53 (m, 2H), 4.68 (t, 7=6.3 Hz, 2H), 3.91 (q, 7= 6.1Hz, 2H), 2.52(s, 3H) 50 sn ₃ Η Τι Τ Η ₂ Ν_ Ν^/χ^Ν,^Α^ AJA ⁰ Ν=< ΗΝ^ 413.9 1.05 δ 12.99-12.71 (m, 1H), 9.17 -9.12(m, 1H), 8.92 (d, 7=4.7 Hz, 1H), 8.71 (s, 1H), 7.93 7.88 (m, 2H), 7.77 (d, 7=5.0 Hz, 1H), 7.75 - 7.57 (m, 2H), 6.96 - 6.78 (m, 2H), 6.73 (s, 1H), 4.66 (brt, 7=6.1 Hz, 2H), 3.89 (q, 7 =5.8Hz, 2H), 2.69(s, 3H) 51 Ν DOS ₃ Η μ Τ Η ₂ Ν__ ΑΑ ° A/ Ν=( ΗΝ^ 430.2 0.96 δ 8.68 (s, 1H), 8.63 - 8.58 (m, 1H), 7.93 - 7.90 (m, 2H), 7.81 (d, 7=9.6 Hz, 1H), 7.70-7.59 (m, 2H), 6.98 (d , 7=9.6 Hz, 1H), 6.83 - 6.59 (m, 3H), 4.64 (t, 7=6.3 Hz, 2H), 3.87-3.81 (m, 2H), 3.70 (s, 3H) 52 n ιι 1 Η ₂ Ν Ν, \___// Ν ητ ° Ο Ν=< ΗΝ^ 414.3 1.04 δ 9.06 (brt, 7=5.6 Hz, 1H), 8.97 (s, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.88 (br d, 7=7.3 Hz, 2H), 7.77 - 7.50 (m, 2H), 6.69 (brs, 1H), 4.62 (brt, 7=5.6 Hz, 2H), 3.85 (brd, 7=5.8 Hz, 2H), 2.53 (s, 3H) 53 Α^Α ^{0 F} Ν=< ΗΝ^ 416.9 1.09 δ 13.87 - 12.93 (m, 1H), 9.81 -9.11 (m, 2H), 9.01 -8.94 (m, 2H), 8.46 (br d, 7=4.4 Hz, 1H), 8.16-8.06 (m, 2H), 7.90 - 7.79 (m, 3H), 7.66 (dt, 7=8.4, 4.1Hz, 1H), 6.78 (s, 1H), 4.71 (brt, 7=5.8 Hz, 2H), 3.89 (q, 7=5.9 Hz , 2H) 54 ^н τΑ and bR-./^/M^A^iA \ // Ν γ F Άλ ⁰ Αζ Ν=< ΗΝ^ 416.8 1.13 δ 13.81 - 13.44 (m, 1H), 9.92 -9.71 (m, 1H), 9.42-9.23 (m, 1H), 9.19 (brt, 7=5.8 Hz, 1H), 8.99 (s, 1H), 8.69 - 8.65 (m, 1H), 8.13 - 8.06 (m, 2H), 7.88 (brd,7=8.3 Hz, 1H), 7.82 (brs, 1H), 7.78 (brd, 7=9.9 Hz, 1H), 7.59-7.51 ( m, 1H), 6.78 (s, 1H), 4.73 (br t, 7=5.6 Hz, 2H), 3.92 (q, 7=5.5 Hz, 2H)

- 56 042018

55 F n ^Η 2 ^Ν .+ _Ν ^Ν^^ ^Ν Γ~/ ° Ν=( ΗΝ^ 417.1 1.12 δ 13.60-12.92 (m, 1H), 9.91 - 9.60 (m, 1H), 9.28 - 9.06 (m, 1H), 9.01 (brt, 7=5.6 Hz, 1H), 8.97 (s, 1H), 8.19-8.06 (m, 3H), 7.92 (br d, J=1.Ί Hz, 1H), 7.88 (br d, 7=8.0 Hz, 1H), 7.85 -7.77 (m, 1H), 7.41 (brd,7=8.8 Hz, 1H), 6.78 (s, 1H), 4.72 (brt, 7=5.8 Hz, 2H), 3.90 (q, 7=6.1 Hz, 2H) 56 CH ₃ nV ^{CF3 Η} II 1 Η ₂ Ν__ ^N vV ° yy Ν=ξ ΗΝ^ 481.3 1.38 5 13.75 - 12.92 (m, 1H), 9.92 -9.57(m, 1H), 9.46-9.17 (m, 1H), 9.16-9.09 (m, 1H), 8.99 (s, 1H), 8.27 (d, 7= 8.3 Hz, 1H), 8.14 - 8.06 (m, 2H), 7.96 (brd, 7=8.0 Hz, 1H), 7.88 (brd, 7=8.3 Hz, 1H), 7.84 - 7.79 (m, 1H), 6.78 ( s, 1H), 4.74 (brt, 7=5.8 Hz, 2H), 3.94 (q, 7=6.1 Hz, 2H), 2.69 (s, 3H) 57 n |H Η ₂ Ν_Ν^ _Ν χΧ^Ν _χ 7\ _;ί ί< 0 OH Ο Ν=< ΗΝ^ 429.0 0.87 5 9.10-9.03 (m, 1H), 8.71 (s, 1H), 8.54 (brd,7=4.6 Hz, 1H), 7.99 (s, 1H), 7.93 - 7.86 (m, 2H), 7.62 (br s, 1H), 7.50 (brd, 7=4.3 Hz, 1H), 6.73 (br s, 1H), 4.69 - 4.63 (m, 2H), 4.60 (br d, 7=5.2 Hz, 2H), 3.90 (br d, 7=5.5Hz, 2H) 58 ^.,ΟΒη Η ϊΓΥ Η ₂ Ν__ ^N Cv ⁰ О Ν=( ΗΝ^ 505.0 1.47 5 8.96 (s, 1H), 8.93 (brt, 7=5.8 Hz, 1H), 8.34 (br s, 1H), 8.11 (brs, 1H), 8.08 (br d, 7=7.9 Hz, 1H), 7.95 ( br d, 7=8.5 Hz, 1H), 7.87 (brd, 7=7.6 Hz, 1H), 7.82 (br s, 1H), 7.59 (br d, 7=8.5 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.40 (brt, 7=7.3 Hz, 2H), 7.377.31 (m, 1H), 6.78 (br s, 1H), 5.24 (s, 2H), 4.71 (brt, 7=5.5 Hz, 2H) , 3.90 (br d, 7=5.8 Hz, 2H) 59 ^OCH ₃ ^Η ιι 1 \~/ ⁰ yy Ν=< ΗΝ^ 429.0 1.23 5 8.90 - 8.83 (m, 1H), 8.72 (s, 1H), 8.27 (brs, 1H), 7.98 (br d,7=8.5 Hz, 1H), 7.92 (brd, 7=7.3 Hz, 2H), 7.64 (br s, 1H), 7.52 (brdd, 7=8.4, 2.0 Hz, 1H), 6.74 (br s, 1H), 4.65 (brt, 7=5.8 Hz, 2H), 3.91 3.84 (m, 5H)

- 57 042018

60 Cl ^H A n _ h nA N \—/ /^\ ⁰ O N=A~^ ^ην Ά 433.1 1.25 5 9.04-8.95 (m, 2H), 8.168.07 (m, 2H), 8.07-8.01 (m, IH), 7.97 (brd,7=7.3 Hz, IH), 7.88 (br d, 7=7.3 Hz, IH), 7.83 (br s, IH), 7.73 (br d, 7=7.9 Hz, IH), 6.78 (br s, IH), 4.73 (brt, 7=5.6 Hz, 2H), 3.91 (brd, 7= 6.1Hz, 2H) 61 η Ό cha^o (at N=< HN^ 433.3 1.20 5 9.18 (brt, 7=5.3 Hz, IH), 8.96 (s, IH), 8.60 (brd,7=5.2 Hz, IH), 8.13 - 8.04 (m, 2H), 7.98 (s, IH), 7.87 ( br d, 7=7.9 Hz, IH), 7.81 (brs, IH), 7.75 (brd,7=4.0 Hz, IH), 6.78 (br s, 1H), 4.73 (brt, 7=5.3 Hz, 2H), 3.92 (brd, 7=5.5Hz, 2H) 62 XF ₃ H II IH ₂ N__ νΑ^ O yy nA HN A 467.1 1.37 5 9.33 - 9.26 (m, IH), 9.02 (s, IH), 8.98 (s, IH), 8.41 (brd, 7=7.9 Hz, IH), 8.18 (brd, 7=8.2 Hz, IH), 8.12 ( brs, IH), 8.08 (brd,7=8.2 Hz, IH), 7.91 -7.80 (m, 2H), 6.78 (brs, IH), 4.74 (brt, 7=5.5 Hz, 2H), 3.94 (br d, 7=5.5Hz, 2H) 63 °^OCH ₃ Y N _ H nA 2 — N^^N jl / N \—/ yy ⁰ O N=(^ ^ην Ά 457.4 1.01 5 8.95 - 8.89 (m, IH), 8.72 (s, IH), 8.25-8.15 (m, 3H), 7.93 -7.86 (m, 2H), 7.69(br s, IH), 7.60 (br d, 7= 7.6 Hz, IH), 6.73 (s, IH), 4.69 (brt, 7=5.6 Hz, 2H), 3.97-3.90 (m, 2H), 3.89 (s, 3H) 64 h TiAr H ₂ N_ Ν^χ-χ^Ν-Τ^^- ^{1 n} A/ ⁰ yy nA hn A 424.4 0.98 5 9.31 (brt, 7=5.5 Hz, IH), 9.10 (s, IH), 8.97 (s, IH), 8.50 (brd, 7=7.9 Hz, IH), 8.13 (brd,7=8.2Hz, IH) , 8.08 (br d, 7=7.9 Hz, IH), 7.87 (br d, 7=7.0 Hz, 2H), 6.77 (brs, IH), 4.73 (brt, 7=5.6 Hz, 2H), 3.93 (brd, 7=5.8Hz, 2H) 65 OCH ₃ ^Η Λ n _ h nA NX-N _x II N \—/ kU ⁰ yy , ⁿ A ^ην Ά 429.3 1.19 5 8.72 (s, 2H), 7.92 - 7.82 (m, 3H), 7.77 - 7.57 (m, 3H), 7.00 (d, 7=8.2 Hz, IH), 6.73 (s, IH), 4.66 (brt, 7 =6.0Hz, 2H), 3.89(brd,7=6.1Hz, 2H), 3.87(s, 3H)

- 58 042018

66 ffY 0 F ABOUT N=< HN^ 435.3 0.96 δ 8.99 (s, 1H), 8.97 - 8.93 (m, 1H), 8.55 (brs, 1H), 8.168.02 (m, 3H), 7.89 (br d, 7=7.9 Hz, 1H), 7.83 (brs, 1H), 6.78 (brs, 1H), 4.71 (br s, 2H), 3.88 (br d, 7=5.2 Hz, 2H) 67 /^/OCF ₃ N ^H II 1 ^h ₂ n ⁰ N=< HfQ 483.3 1.26 δ 9.12 (brt, 7=5.3 Hz, 1H), 8.71 (s, 2H), 8.15 (brd, 7=8.5 Hz, 1H), 8.06 (br d, 7=8.8 Hz, 1H), 7.92 - 7.85 (m , 2H), 7.69 (brs, 1H), 7.61 (brd,7=5.5 Hz, 1H), 6.73 (s, 1H), 4.66 (brt, 7=5.8 Hz, 2H), 3.89 (br q, 7=5.5 Hz, 2H) 68 ^Η \θ ⁰ w N =/ HN^ 417.3 1.12 6 8.68 (s, 1H), 8.32 (brt, 7=5.5 Hz, 1H), 7.95 - 7.84 (m, 2H), 7.77 - 7.55 (m, 2H), 6.73 (brs, 1H), 4.59 (brt, 7 =5.8 Hz, 2H), 3.78 (br d, 7=5.8 Hz, 2H), 2.47 (s, 3H), 2.35 (s, 3H) 69 ^N L N. Η NO /—C N'X^I\L // Δ N \—/ )==/ o N=/^ HN^ 389.3 0.86 6 9.07-8.97 (m, 2H), 8.91 (br s, 1H), 8.12 (brs, 1H), 8.05 (brd,7=7.9 Hz, 1H), 7.83 (br s, 2H), 6.83 (s, 1H ), 6.78 (br s, 1H), 4.68 (brt, 7=5.3 Hz, 2H), 3.85 (brq, 7=5.3 Hz, 2H) 70 ⁿ / ^H /-f N-^-N // 7 N )=/ Y^Y YY ⁰ yj N=/ HN^ 400.3 0.79 6 9.22 (brs, 1H), 8.94 (brd, 7=4.6 Hz, 3H), 8.12-8.07 (m, 1H), 8.05 (brd,7=8.2Hz, 1H), 7.83 (br s, 2H), 7.67 (br t, 7=4.6 Hz, 1H), 6.77 (br s, 1H), 4.76 -4.68 (m, 2H), 3.95 -3.88 (m, 2H) 71 ^F ^ ^c yo /y ⁰ yy N =/ HN^/ 471.2 1.21 6 8.96 (s, 1H), 8.89 (brt, 7=5.6 Hz, 1H), 8.10 (brd, 7=8.5 Hz, 2H), 7.90 (br d, 7=8.2 Hz, 1H), 7.82 (brs, 1H ), 6.79 (s, 1H), 4.68 (brt, 7=5.5 Hz, 2H), 3.84 (br d, 7=5.8 Hz, 2H), 2.52 (br s, 3H) 72 /^/Cl η ΐΎ H ₂ N .Ν^/Χ/Νγ// YuU ° O N=< HN^ 433.3 1.25 6 9.09 (brt, 7=5.5 Hz, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.10 (brd, 7=7.9 Hz, 1H), 8.02 (brd, 7=8.5 Hz, 1H) , 7.93 - 7.86 (m, 2H), 7.63 (br s, 1H), 6.73 (br s, 1H), 4.65 (brt, 7=5.8 Hz, 2H), 3.88 (br d, 7=5.8 Hz, 2H)

-59042018

73 H A ^Νν^/χ^Ν^ΑΑ n^v ° nA hnA 400.2 0.97 δ 9.56 (brt, 7=5.6 Hz, 1H), 9.39 (brd, 7=4.9 Hz, 1H), 8.87 (brs, 1H), 8.17 (brd, 7=8.2 Hz, 1H), 8.00 (brd, 7 =8.2 Hz, 2H), 7.89 (brdd, 7=8.2, 5.2 Hz, 1H), 7.76 (br s, 2H), 6.76 (br s, 1H), 4.73 (br t, 7=5.6 Hz, 2H), 3.95 (brd, 7=5.8Hz, 2H) 74 n II I h ₂ n ν^,/^νΑΑ \ // N γ CC ° nA hnA 416.1 1.19 5 8.71 (s, 1H), 8.53 (brs, 1H), 7.94 - 7.84 (m, 2H), 7.69 (br s, 1H), 7.63 (br d, 7=7.6 Hz, 1H), 7.59 (brt, 7 =7.2 Hz, 1H), 7.55 - 7.45 (m, 1H), 7.32 -7.21 (m, 2H), 6.74 (s, 1H), 4.63 (brt, 7=5.6 Hz, 2H), 3.82 (br d, 7 =5.8Hz, 2H) 75 h Cl H ₂ N_ N-. _N /\ _/ N _x AA /y ⁰ nA hn A 400.2 1.00 5 9.30 (br s, 2H), 9.04 (brd, 7=4.9 Hz, 1H), 8.71 (s, 1H), 7.98 (br d, 7=4.6 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.69 (br s, 1H), 7.63 (br d, 7=6.7 Hz, 1H), 6.73 (s, 1H), 4.66 (brt, 7=5.8 Hz, 2H), 3.90 (br d, 7=5.8 Hz, 2H) 76 ^H2N \z _/ ⁿ 'n'^^Y^n^ ^{CH3 n} C/ ⁰ O nA hn A 403.4 0.91 5 8.69 (s, 1H), 8.49 (brt, 7=5.3 Hz, 1H), 8.43 (s, 1H), 7.95 - 7.88 (m, 2H), 7.77 7.58 (m, 2H), 6.74 (br s, 1H ), 4.60 (brt, 7=6.0 Hz, 2H), 3.80 (br d, 7=5.8 Hz, 2H), 2.43 (s, 3H) 77 IZ Z -* TI Ί > ^Z z0 T 415.8 1.23 5 8.80 - 8.75 (m, 1H), 8.71 (s, 1H), 7.93 - 7.87 (m, 2H), 7.69 (br s, 1H), 7.65 (br d, 7=7.6 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.54.7.47 ( _m , 1H), 7.37 (br t, 7=7.6 Hz, 1H), 6.73 (s, 1H), 4.62 (brt,7=5.5 Hz, 2H), 3.82 (br d, 7=5.8Hz, 2H) 78 ⁿ An H ₂ N N. X _N ' V o X \( H ₃ CN % Z\ ^N= \ A N=( HN A 508.1 0.96 5 8.87 (s, 1H), 8.71 (s, 1H), 8.28 - 8.23 (m, 1H), 7.89 (br d, 7=4.9 Hz, 2H), 7.75-7.69 (m, 2H), 7.61 (brs, 1H), 7.40 (brd, 7=7.0 Hz, 1H), 6.90 (br d, 7=8.2 Hz, 1H), 6.73 (brs, 1H), 5.97 (s, 1H), 4.65 (brs, 2H), 3.89 (br d, 7=5.5 Hz, 2H), 3.54 (s, 3H), 1.96 (s, 3H)

- 60 042018

79 n if^ H ₂ N N. \_/ N - γ - OCH ₃ ZV ⁰ W N=< HN A 428.3 1.16 5 8.70 (s, IH), 8.66 (brt, 7=5.0 Hz, IH), 7.94 - 7.87 (m, 2H), 7.61 (brs, IH), 7.39 - 7.30 (m, 3H), 7.07 (br d, 7=7.3 Hz, IH), 6.73 (s, IH), 4.62 (brt,7=5.5 Hz, 2H), 3.81 (brd, 7=5.2 Hz, 2H), 3.75 (s, 3H) 80 H Г\ ^НзС Λ \ II //^ CH3 / WOO ⁷ J HNW 520.1 1.41 5 8.74 (s, IH), 8.06 (brt, 7=5.3 Hz, IH), 7.97 - 7.89 (m, 2H), 7.73 (s, IH), 7.66 (br s, IH), 6.74 (br s, IH ), 4.63 (brt, 7=5.5 Hz, 2H), 3.85 (br d, 7=5.8 Hz, 2H), 1.47 (s, 9H) 81 7 \=^ o OCH ₃ N=< HN A 428.1 1.23 5 8.98 (s, IH), 8.37 - 8.32 (m, IH), 8.11 (brd,7=8.2 Hz, 2H), 7.89 (br d, 7=7.6 Hz, IH), 7.83 (br s, IH), 7.67 (br d,7=7.3 Hz, IH), 7.44 (brt, 7=7.8 Hz, IH), 7.08 (brd, 7=8.2 Hz, IH), 7.00 (brt, 7=7.3 Hz, IH), 6.79 (br s, IH), 4.71 (brt, 7=4.9 Hz, 2H), 3.89 (br d, 7=5.2 Hz, 2H), 3.74 (s, 3H) 82 WW'fO'C! ^ν ΓΊ/ ° yy nA HnA 432.0 1.24 5 8.79 (brt,7=5.2Hz, IH), 8.70 (s, IH), 7.92 - 7.86 (m, 2H), 7.81 (s, IH), 7.74 (brd, 7=7.6 Hz, IH), 7.69 ( br s, IH), 7.61 (brd,7=7.9 Hz, IH), 7.58 (br d, 7=7.9 Hz, IH), 7.48 (t, 7=7.8 Hz, IH), 6.73 (s, IH), 4.62 (brt, 7=5.6Hz, 2H), 3.82 (brd, 7=5.5Hz, 2H) 83 h О H ₂ N N- AxN \__// N γ yj ⁰ NA HN A 400.3 1.02 5 9.22-9.13 (m, 2H), 8.86 (s, IH), 8.70 (br s, 2H), 7.927.86 (m, 2H), 7.69 (br s, IH), 7.60 (br d, 7=7.9 Hz, IH), 6.73 (s, IH), 4.66 (brt, 7=5.8 Hz, 2H), 3.93 - 3.86 (m, 2H) 84 H H ₂ N N.^N^A/N \ // N γ ^N Cv ⁰ nA hnA 389.3 0.79 5 8.99 (brs, IH), 8.85 (brs, 2H), 8.55 (s, IH), 8.15 (brs, IH), 8.10 (brd,7=7.9 Hz, IH), 7.87 (br d, 7=19.5 Hz , 2H), 7.74 (s, IH), 6.79 (br s, IH), 4.68 (br s, 2H), 3.83 (br d, 7=4.9 Hz, 2H)

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85 FyyCl ^N f-/ ⁰ O Ν=X ΗΝ^ 451.3 1.36 5 8.97 (brs, 1H), 8.68 (s, 1H), 8.53 (brs, 1H), 8.19 (brd, 7=10.1 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.68 (br s, 1H) , 7.61 (brd, 7=7.3 Hz, 1H), 6.73 (br s, 1H), 4.63 (brs, 2H), 3.85 (br d, 7=5.2 Hz, 2H) 86 ,-S___, Η fl Χ./Χ ν^Ρ ° uu Ν=( ΗΝ^ 482.2 0.95 δ 8.81 (brt, 7=5.6 Hz, 1H), 8.75 (s, 1H), 8.72 (brd,7=4.9 Hz, 2H), 8.45 (s, 1H), 7.95 (brd,7=4.9 Hz, 2H) , 7.93 7.87 (m, 2H), 7.69 (br s, 1H), 7.61 (br d, 7=7.9 Hz, 1H), 6.73 (s, 1H), 4.68 (brt, 7=6.0 Hz, 2H), 3.90 (brd, 7=4.9Hz, 2H) 87 Μ Η ₂ Ν Ν^ _ν χ^^ Ν.χ^/ ^{Ν CH} 3 ρ-ρ ° Ο Ν=< ΗΝ^ 402.0 0.72 5 8.95 (s, 1H), 8.27 (brt, 7=5.0 Hz, 1H), 8.13 - 8.06 (m, 2H), 7.89 (br d, 7=8.2 Hz, 1H), 7.81 (brs, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 6.79 (s, 1H), 4.67 (brt, 7=5.6 Hz, 2H), 3.84 (br d, 7=5.8 Hz, 2H), 3.66 (s, 3H ) 88 C ^S ° O N=< HN^ 439.2 1.16 5 8.95 (s, 1H), 8.79 (brt, 7=5.5 Hz, 1H), 8.21 (s, 1H), 8.09 (br d, 7=6.7 Hz, 2H), 7.88 (brd, 7=8.2 Hz, 1H ), 7.81 (s, 1H), 6.78 (s, 1H), 4.68 (brt,7=5.5 Hz, 2H), 3.85 (br d, 7=5.5 Hz, 2H) 89 ^νζΝ'Ν^γΧΧ ⁿ C/ ⁰ yY N=< HN^ 451.0 1.27 5 9.00 (brt, 7=5.8 Hz, 1H), 8.73 (s, 1H), 8.11 - 8.04 (m, 2H), 7.93 (brd,7=8.2 Hz, 2H), 7.84 - 7.58 (m, 2H), 6.74 (brs, 1H), 4.66 (brt, 7=5.8 Hz, 2H), 3.87 (br d, 7=5.8 Hz, 2H) 90 H H ₂ N x-x xC χ*χ ² \__J NTN CF ₃ ^N w ¹ О N =( HN^ 467.1 1.30 5 8.99 (s, 2H), 8.30 - 8.22 (m, 2H), 8.10 (brdd, 7=13.7, 7.6 Hz, 3H), 7.88 (brd,7=7.6Hz, 1H), 7.83 (brs, 1H), 6.78 (br s, 1H), 4.75 (brt, 7=5.8 Hz, 2H), 3.94 (br d, 7=5.8 Hz, 2H)

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91 ^{Η Ν} _Η “·”~γν ^N d/ ⁰ О N=( HN^ 485.3 1.18 δ 9.09 (brt, J=5.5 Hz, 1H), 8.87 (s, 1H), 8.70 (s, 1H), 8.45 (br d, 7=10.4 Hz, 1H), 7.93 - 7.86 (m, 2H), 7.69 (br s, 1H), 7.61 (br d, 7=7.6 Hz, 1H), 6.73 (d, 7=1.5 Hz, 1H), 4.65 (brt, 7=5.8 Hz, 2H), 3.88 (br d, 7 =6.1Hz, 2H) 92 ^Hg \A^ ^U yY N^ ¹ 0 Cl n4 HN^ 432.9 1.05 δ 8.97 (s, 1H), 8.93 - 8.87 (m, 1H), 8.53 (dd, 7=4.5, 1.2 Hz, 1H), 8.16-8.06 (m, 2H), 8.01 -7.96 (m, 1H), 7.89 (br d, 7=7.2 Hz, 1H), 7.85 - 7.77 (m, 1H), 7.53 (dd, 7=8.3, 4.7 Hz, 1H), 6.78 (brs, 1H), 4.75 -4.64 (m, 2H) , 3.94-3.83 (m, 2H) 93 °\ / \ h ₂ n ^nh ⁰ Ln / Cj> HN J 406.4 1.02 δ 8.88 (s, 1H), 8.12-8.08 (m, 2H), 7.94 - 7.87 (m, 2H), 7.81 (brs, 1H), 6.79 (s, 1H), 4.58 (q, 7=5.6 Hz, 2H ), 3.48 (br s, 4H), 3.39 (brt, 7=10.2 Hz, 1H), 1.77 - 1.67 (m, 2H), 1.51 - 1.39 (m, 3H), 1.29-1.17 (m, 1H) 94 ^H π 1 H ₂ N__ ⁿ C/ ° yj* N =< HN^ 413.0 1.04 6 9.01-8.95 (m, 1H), 8.69 (s, 1H), 8.44 (s, 1H), 7.89 (brs, 3H), 7.77 (br d, 7=8.2 Hz, 1H), 7.69 (br s, 1H ), 7.62 (br d, 7=7.6 Hz, 1H), 6.73 (s, 1H), 4.65 (brt, 7=5.6 Hz, 2H), 3.88 (brd, 7=3.7 Hz, 2H), 2.35 (s, 3H) 95 H П Q H ₂ N Ν^/^Ν,Λ/ ^{0 ν} Γ~/ ° N=< HN^ 405.1 0.88 δ 9.13 (d, 7=1.5 Hz, 1H), 8.74 (brt, 7=5.6 Hz, 1H), 8.70 (s, 1H), 8.29 (d, 7=1.5 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.69 (br s, 1H), 7.62 (br d, 7=7.3 Hz, 1H), 6.73 (d, 7=1.5 Hz, 1H), 4.64 (brt, 7=6.0 Hz, 2H), 3.86 ( brd, 7=6.1Hz, 2H) 96 CH ₃ ⁿ 15 H ₂ N Ν _ηι ζ^Ν.Ά/ \___// N ]Г b ⁿ C/ ⁰ y^ N =< HN^ 419.3 1.14 δ 9.00 (brt, 7=5.9 Hz, 1H), 8.89 (s, 1H), 8.08-8.01 (m, 2H), 7.81 (brdd, 7=15.1, 6.6 Hz, 2H), 7.56 (s, 1H), 6.77 (s, 1H), 4.69 (brt, 7=5.9 Hz, 2H), 3.89 - 3.83 (m, 2H), 2.40 (s, 3H)

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97 Η IL ⁰ N=< HN^ 405.2 1.00 5 9.14-9.07 (m, 1H), 8.97 (s, 1H), 8.15-8.05 (m, 2H), 8.04 -7.97 (m, 2H), 7.88 (br d, 7=5.8 Hz, 1H), 7.83 ( brs, 1H), 6.79 (brs, 1H), 4.72 (br t, 7=5.6 Hz, 2H), 3.89 (br d, 7=5.2 Hz, 2H) 98 ² \___/} N P ^N d/ ° st N=\ HN^ 466.3 1.05 5 9.19 (brt, 7=5.5 Hz, 1H), 9.12 (brd, 7=7.0 Hz, 1H), 8.99 (d, 7=3.7 Hz, 2H), 8.21 8.15 (m, 1H), 8.10 (brs, 1H ), 8.08 (brd, 7=8.2 Hz, 1H), 7.90-7.84 (m, 2H), 7.82 (br s, 1H), 7.58 (brt, 7=6.9 Hz, 1H), 6.78 (s, 1H), 4.74 (brt, 7=5.5Hz, 2H), 3.99 (brd, 7=5.8Hz, 2H) 99 H ₃ c n 1Λ ⁰ N=< HN^ 402.2 0.79 5 8.76 - 8.62 (m, 2H), 7.93 7.86 (m, 2H), 7.69 (br s, 1H), 7.62 (br d, 7=7.9 Hz, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.73 (s, 1H), 4.61 (brt, 7=5.8 Hz, 2H), 3.90 (s, 3H), 3.80 (br d, 7=5.8 Hz, 2H) 100 CO oh oh IZ X T Ί T 452.3 0.98 5 9.83 (brd,7=5.5 Hz, 1H), 9.01 (s, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 8.03 (brd,7=8.2 Hz, 1H), 7.94 (s, 1H), 7.88 (brdd, 7=12.5, 7.9 Hz, 2H), 7.83 - 7.78 (m, 2H), 7.41 (br t, 7=7.8 Hz, 1H), 6.78 (s, 1H), 4.81-4.75 ( m, 2H), 4.07 (br d, 7=5.5 Hz, 2H), 3.87 (s, 3H) 101 N / \^N H ₂ Nn . _N N ° N=< HN.^ 439.3 1.04 5 9.25 (brd, 7=7.0 Hz, 1H), 8.73 (s, 1H), 8.62 (brd,7=3.4 Hz, 1H), 8.57 (s, 1H), 8.18 (brt, 7=5.2 Hz, 1H) , 7.927.86 (m, 2H), 7.69 (br s, 1H), 7.61 (br d, 7=7.6 Hz, 1H), 7.21 (dd, 7=6.7, 4.3 Hz, 1H), 6.73 (s, 1H ), 4.67 (brt, 7=5.6 Hz, 2H), 3.96 (br d, 7=5.5 Hz, 2H)

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- 1 H-isoindole-1-one.

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (50 mg, 0.096 mmol) in DMF ( 479 µl) N,N-diisopropylethylamine (84 µl, 0.48 mmol) and methyl 2(bromomethyl)benzoate (22.0 mg, 0.096 mmol) were added. The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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-minute hold at 0% B, 0-40% B for 20 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS and UV signals.

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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%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 7.88 (br s, 1H), 7.86 (br d, J=7.7 Hz, 1H), 7.767.52 (m, 5H), 7.48-7.43 (m, 1H), 6.72 (br s, 1H), 6.82-6.70 (m, 2H), 4.73 (br t, J=5.8 Hz, 2H), 4.33 (s, 2H), 4.12 (br t , J=5.5 Hz, 2H). Analytical LC/MS conditions: Waters XBridge C18 column, 2.1x50 mm, particles 1.7 µm; 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 for 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 410.0 [M+H]+; RT: 1.11 min.

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.

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amineα, 2 TFA (50 mg, 0.096 mmol) in DMF ( 479 μl) N,N-diisopropylethylamine (84 μl, 0.48 mmol) and methyl 2(bromomethyl)-5-fluorobenzoate (23.7 mg, 0.096 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with H2O (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 , 200x19 mm, particles 5 µm; 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 min hold at 4% B, 4-44% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS 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)-6fluoroisoindolin-1-one, TFA (16.1 mg, 30%). 1Н NMR (500 MHz, DMSO-d ₆ ) 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, 1H), 7.47-7.33 (m, 2H), 6.77 (s, 1H), 4.81 (br t, J=5.6 Hz, 2H), 4.39 (s, 2H), 4.14 (br t, J=5.5 Hz, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 to 100% B over 3 min, then hold for 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 428.3 [M+H] ⁺ ; RT: 1.35 min.

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.

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (50 mg, 0.096 mmol) in DMF ( 479 µl) N,N-diisopropylethylamine (84 µl, 0.479 mmol) and methyl 2(bromomethyl)-4-chlorobenzoate (25.3 mg, 0.096 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ O (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, 200x19 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 min hold at 11% B, 11-51% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS 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)5-chloroisoindolin-1-one (11.9 mg, 28%). 1Н NMR (500 MHz, DMSO-d ₆ ) 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 method LC/MS: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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: from 0

- 65 042018 to 100% B for 3 min, then hold 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 444.1 [M+H]+; RT: 1.37 min.

Example 105 Preparation of 2-(2-{[(2-methylphenyl)methyl]amino}ethyl)-7-(1H-pyrazol-3-yl)-2Hpyrazolo[3,4-c]quinoline-4-amine

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (35 mg, 0.067 mmol) in DMF ( 336 µl) 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 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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-minute hold at 0% B, 0-60% B for 25 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on 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[3.4c] quinoline-4-amine, 2 TFA (17.5 mg, 40%). Ή NMR (500 MHz, DMSO-d ₆ ) 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, 2.1x50 mm, particles 1.7 µm; 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 for 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 398.1 [M+H]+; RT: 1.08 min.

The compounds of examples 106-112 were prepared according to synthetic procedures similar to those described for example 105 from the appropriate starting materials. For examples 106 and 108, triethylamine (2.5 eq.) was added to the starting material before adding other reagents. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 for 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

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Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 106 ⁿ P ^Ν \— yy N=< HN^ 402.2 0.84 5 8.66 (s, 1H), 7.92 (d, 7=8.1 Hz, 1H), 7.89 (s, 1H), 7.67 (br s, 1H), 7.62 (brd, 7=7.8 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.13 -7.07 (m, 2H), 6.99 (brt, 7=8.5 Hz, 1H), 6.71 (s, 1H), 6.53 (br s, 2H), 4.51 (t, 7=6.0 Hz , 2H), 3.75 (s, 2H), 3.06 (t, 7=6.1 Hz, 2H) 107 n fl I H ₂ N__ W N=< HN^ 418.2 0.92 5 8.66 (s, 1H), 7.93 (d, 7=8.1 Hz, 1H), 7.90 (d, 7=1.1 Hz, 1H), 7.67 (d, 7=1.7 Hz, 1H), 7.64 (dd, 7= 8.1, 1.4 Hz, 1H), 7.30 (s, 4H), 6.71 (d, 7=2.1 Hz, 1H), 4.51 (t, 7=6.1 Hz, 2H), 3.72 (s, 2H), 3.07 (t, 7=6.1Hz, 2H) 108 Η ΡΊ h ₂ n N=< HN^ 384.1 0.98 5 8.69 (s, 1H), 7.92 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.69 (br s, 1H), 7.62 (brd, 7=8.5 Hz, 1H), 7.30 - 7.24 (m, 4H), 7.23 -7.17(m, 1H), 6.73 (d, 7=1.9 Hz, 1H), 6.81 -6.65 (m, 2H), 4.50 (t, 7=6.1 Hz, 2H), 3.72 ( s, 2H), 3.04 (brt, 7=6.2Hz, 2H) 109 ^Η Λ H )=( ^H 3 ^C о N=Z HN^ 336.0 1.04 5 8.67 (s, 1H), 7.92 (d, 7=8.0 Hz, 1H), 7.89 (d, 7=1.4 Hz, 1H), 7.67 (s, 1H), 7.64-7.61 (m, 1H), 6.71 ( d, 7=2.0 Hz, 1H), 4.47 (t, 7=6.3 Hz, 2H), 3.09 (t, 7=6.4 Hz, 2H), 2.792.73 (m, 1H), 0.97 (d, 7=6.3 Hz, 6H) BY N n II Ί H ₂ NN . _N /\/ N N=< HN^ 385.0 0.92 5 8.68 (s, 1H), 8.46 (s, 1H), 8.39 (d, 7=4.7 Hz, 1H), 7.93 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.70 - 7.66 ( m, 2H), 7.63 (d, 7=7.7 Hz, 1H), 7.29 (dd, 7=7.8, 4.8 Hz, 1H), 6.73 (d, 7=1.7 Hz, 1H), 4.51 (brt, 7=5.9 Hz, 2H), 3.04 (brt, 7=5.8Hz, 3H) 111 ^H2N \ N _s H 7...../ HnQ ^H 3 ^C0 414.1 0.99 5 8.69 (s, 1H), 7.92 (d, 7=8.3 Hz, 1H), 7.89 (s, 1H), 7.69 (br s, 1H), 7.62 (brd,7=8.3 Hz, 1H), 7.21 (d , 7=8.5 Hz, 2H), 6.84 (d, 7=8.5 Hz, 2H), 6.73 (s, 1H), 6.80 -6.70 (m, 2H), 4.51 (brt, 7=6.2 Hz, 2H), 3.70 (s, 3H), 3.68 (s, 2H), 3.05 (brt, 7=6.1Hz, 2H) 112 η Ό H ₂ N N=< HN^ 385.3 0.94 5 8.75 (s, 1H), 8.49 (brd, 7=4.3 Hz, 1H), 7.95 (brd, 7=7.9 Hz, 1H), 7.92 (br s, 1H), 7.72 (br d, 7=7.6 Hz, 2H), 7.66 (brd, 7=7.3 Hz, 1H), 7.37 (br d, 7=7.6 Hz, 1H), 7.30-7.24 (m, 1H), 6.74 (s, 1H), 4.63 4.58 (m, 2H ),3.96(s, 2H), 3.22(brt, 7=6.0Hz, 2H)

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Example 113 Preparation of N{2-[4-amino-7-(III-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2yl]ethyl}methanesulfonamide.

To a solution of 2-(2-aminoethyl)-7-(III-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (35 mg, 0.067 mmol) in DMF ( 224 µl) triethylamine (37.4 µl, 0.269 mmol) was added at room temperature followed by methanesulfonyl chloride (8.1 mg, 0.070 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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-minute hold at 0% B, 0-40% B for 20 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fractions were collected based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. The product was further purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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 min hold at 13% B, 13-36% B for 25 min, then 2 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was started based on 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[3,4c]quinolin-2-yl) ethyl)methanesulfonamide, TFA (6.1 mg, 19%). 1Н NMR (500 MHz, DMSO-d ₆ ) 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, 2.1x 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 to 100% B over 3 min, then hold 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 372 [M+H]+; RT: 0.94 min.

Example 114 Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2yl]ethyl}benzenesulfonamide.

To a solution of 2-(2-aminoethyl)-7-(III-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (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 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 11% B, 11-51% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS 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-2yl) ethyl)benzenesulfonamide (34.3 mg, 80%). ¹ H NMR (500 MHz, DMSO-d ₆ ) 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), 6.686.52 (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, 2.1 x 50 mm, particles 1.7 µm; 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 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 434.3 [M+H]+; RT: 1 min.

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Example 115 Preparation of 3-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}1-phenyl urea

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (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 mixture was stirred at 0°C for 1 h. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 µm; 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 min hold at 8% B, 8-48% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 1-(2-(4amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl) ethyl)-3-phenylurea (16.5 mg, 52%). 1Н NMR (500 MHz, DMSO-d ₆ ) 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), 6.836.75 (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, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 413.1 [M+H]+; RT: 1.14 min.

Example 116 Preparation of 1-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}3,3-dimethyl urea .

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (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 mixture was stirred at 0°C for 30 min, then at room temperature for 1.5 h. The reaction mixture was diluted with H ₂ O (0.2 ml) and DMF (to a total volume of 2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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 min hold at 1% B, 1-41% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was started based on 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[3,4c]quinolin-2-yl) ethyl)-1,1-dimethylurea (20.5 mg, 73%). 1H NMR (500 MHz, DMSO-d ₆ ) 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, 2Н), 3.57-3.52 (m, 2H), 2.75 (s, 6H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 365.3 [M+H]+; RT: 0.89 min.

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Example 117 Preparation of Phenyl N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo-[3,4-c]quinolin-2yl]ethyl} carbamate

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (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 mixture was stirred at 0°C for 30 min. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 μm; 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 min hold at 5% B, 5-45% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on 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%). Ή NMR (500 MHz, DMSO-d ₆ ) 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 VEN C18, 2.1 x 50 mm, particles 1.7 µm; 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: 0-100% B over 3 min, then hold for 0.75 min at 100% B; flow rate: 1.0 ml/min; detection: UV at 220 nm. m/z 414.4 [M+H]+; RT: 1.26 min.

Example 118 Preparation of tert-butyl N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4c]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 (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) were evacuated and refilled with N2, then 1,4-dioxane (864 µl) and H2O (96 µl) were added. The resulting mixture was purged with N2 for 10 min, then 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (6.26 mg, 9.60 µmol) was added. The mixture was purged with N2 for 1 min, then sealed and stirred at 100°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (30 mL) and washed with H2O (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 ₂ SO ₄ , 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, 200x19 mm, particles 5 µm; 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 min hold at 7% B, 7-45% B for 25 min, then 7 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC/MS using the following conditions: column: XBridge Phenyl, 200x19 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 min hold at 9% B, 9-49% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried.

- 70 042018 by centrifugal evaporation to obtain tert-butyl (2- (4-amino-7- (1H-pyrazol-3-yl) -2H pyrazolo [3,4-c] quinolin-2) -yl) ethyl) carbamate ( 5.7 mg, 15%). 1Н 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, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 394.1 [M+H]+; RT: 1.18 min.

Example 119 Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}N-methylacetamide.

Step 1: tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)(methyl)carbamate.

Cesium carbonate (1330 mg, 4 08 mmol), then tert-butyl (2chloroethyl)(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 h, then at 50°C for 16 h. The reaction mixture was diluted with EtOAc (100 ml), washed with 10% aq. LiCl (2x50 ml) and saturated aqueous NaCl (50 ml), dried over Na ₂ SO ₄ and filtered. Celite was added and the mixture concentrated in vacuo. This material was loaded onto the column dry and purified by flash chromatography (40 g silica gel with 25 g solid loading cartridge; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give t-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 corresponds to the ratio of rotamers ~2:1. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

Step 2. tert-Butyl 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)-1Hpyrazole (318 mg, 1.14 mmol) and cesium carbonate (744 mg, 2.28 mmol) was evacuated and refilled with N ₂ , then 1,4-dioxane (6852 μl) and H ₂ O (761 μl) were added. The resulting mixture was purged with N ₂ for 10 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.9 mg, 0.038 mmol) was added. The mixture was sparged with N ₂ for 1 min, then sealed and stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with H ₂ O (100 ml) and saturated aqueous NaCl (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give t-butyl (2-(4-amino-7-(1-(tetrahydro2H-puran-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 corresponds to the ratio of rotamers ~2:1. 1Н NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

Step 3 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[3,4-c]quinolin-2 -yl)ethyl)(methyl)carbamate (304 mg, 0.618 mmol) in CH ₂ Cl ₂ (1546 μl) TFA (1546 μl) was added at room temperature. The reaction mixture was stirred at room temperature

- 71 042018 temperature for 2 h. The reaction mixture was concentrated in a stream of N2 to remove about half the volume, then it was added dropwise to Et ₂ O (20 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x2 ml) to give 2-(2-(methylamino)ethyl)-7-(1Hpyrazol-3 -yl)-2H-pyrazolo[3,4-c]quinolin- 4-amine, 2 TFA (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 , 2Н), 8.19-8.10 (m, 2Н), 7.93 (br d, J=8.0 Hz, 1H), 7.85 (br s, 1H), 6.80 (d, J=2.0 Hz, 1H), 4.85 (brt, J=5.6 Hz, 2H), 3.61 (br s, 2H), 2.70 (br s, 3H). LC-MS m/z 308 [M+H]+.

Step 4 N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-Nmethylacetamide.

To a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (20 mg, 0.037 mmol) acetic acid (2.136 µl, 0.037 mmol) was added to DMF (208 µl) at room temperature followed by Ν,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 h. The reaction mixture was diluted with H ₂ O (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, 200x19 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-minute hold at 0% B, 0-40% B for 20 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on 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]quinoline-2 -yl)ethyl)-N methylacetamide, TFA (14.1 mg, 80%). NMR corresponds to the ratio of rotamers ~2:1. 1Н 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 (brt, J=5.9 Hz, 0.67H), 4.61 (brt, 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 VEN C18, 2.1 x 50 mm, particles 1.7 µm; 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: 0-100% B for 3 min, then hold 0.75 min at 100% B; flow rate: 1.0 ml/min; detection: UV at 220 nm. m/z 350.3 [M+H]+; RT: 0.87 min.

Example 120 Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}N-methylbenzamide.

To benzoic acid (12.6 mg, 0.103 mmol) was added Ν,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 mixture was stirred at room temperature for 5 min, then added dropwise to a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c] quinoline-4-amine, 2 TFA (0.25 M solution in DMF with 0.75 M Ν,N-diisopropylethylamine) (0.374 mL, 0.093 mmol). The clear orange solution was stirred at room temperature for 1 h. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 µm; 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 min hold at 7% B, 7-47% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1Hpyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl) ethyl)-N-methylbenzamide (30.5 mg, 79%). NMR corresponds to the ratio of rotamers ~2:1. 1Н NMR (500 MHz, DMSO-d ₆ ) 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), 4.744.68 (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 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 412.1 [M+H]+; RT: 1.21 min

Example 121 Preparation of 2-{2-[benzyl(methyl)amino]ethyl}-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-72 042018

c]quinoline-4-amine.

To a solution of 2-(2-(methylamino)ethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine at room temperature, 2 TFA (20 mg, 0.037 mmol) in DMF (187 μl) was added benzaldehyde (5.0 μl, 0.049 mmol) followed by sodium triacetoxyborohydride (23.8 mg, 0.112 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (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 , 200x19 mm, particles 5 µm; 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 min hold at 12% B, 12-37% B for 25 min, then 2 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on 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] quinoline-4-amine, TFA (10.0 mg, 50%). Ή NMR (500 MHz, DMSOde) 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 VEN C18, 2.1 x 50 mm, particles 1.7 µm; 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: 0-100% B over 3 minutes, then hold 0.75 minutes at 100% B; flow rate: 1.0 ml/min; detection: UV at 220 nm. m/z 398 [M+H]+; RT: 1.03 min.

- {2-[4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-2 Example 122 Preparation of yl]ethyl}pyrrolidin-2-one.

Step 1 N-(2-[7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-4-chlorobutanamide.

2-(2-Aminoethyl)-7-bromo-2Hpyrazolo[3,4-c]quinoline-4-amine (900 mg, 2.94 mmol, 1 eq.), DCM (30 ml), pyridine (697.6 mg, 8.82 mmol, 3 eq.) and 4-chlorobutanoyl chloride (829.0 mg, 5.88 mmol, 2 eq.). The resulting solution was stirred for 16 hours at room temperature. The reaction was then quenched by adding MeOH. The resulting mixture was concentrated. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (10:1) to give N-(2-[7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)-4- chlorobutanamide (240 mg, 21%) as a light yellow solid. LC-MS m/z [M+H] ⁺ =390.1.

Step 2 1-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)pyrrolidin-2-one.

N-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin2-yl]ethyl)-4-chlorobutanamide (300 mg, 0.73 mmol, 1 eq.) in THF (7 ml). Then t-BuOK (163.9 mg, 1.46 mmol, 2 eq) was added. The resulting solution was stirred for 16 hours at room temperature. Re

- 73 042018 the action was quenched by adding H2O (20 ml). The resulting solution was extracted with ethyl acetate (3x20 ml). The resulting mixture was concentrated. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1) to give 1-(2-[4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2yl]ethyl)pyrrolidine -2-one (200 mg, 73%) as a light yellow solid. LC-MS: (ES, m/z): [M+H]+=374.1.

Step 3 1-[2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl]pyrrolidin-2-one.

1-(2-[4-Amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl)pyrrolidin- 2-one (200 mg, 0.53 mmol, 1 eq.), Cs ₂ CO ₃ (348.3 mg, 1.07 mmol, 2 eq.), 3-(tetramethyl-1,3,2-dioxaborolane- 2-yl)-1Hpyrazole (207.4 mg, 1.07 mmol, 2 eq.), Pd(dppf)Cl ₂ (39.1 mg, 0.05 mmol, 0.1 eq.) in dioxane (5 ml ) and H ₂ O (1.25 ml). The resulting solution was stirred for 16 h at 80°C. The resulting mixture was cooled to room temperature and concentrated. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1). The crude product was purified by preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (15% PhaseB to 40% in 7 min); detector, UV. This provided 1-[2-[4amino-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-d ₆ , 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, 2H), 3.74-3.71 (m, 2H), 3.28-3.25 (m, 2H), 2.18

2.14 (m, 2H), 1.96-1.83 (m, 2H). LC methods: Column: Kinetex EVO 3.0x50 mm, particles 2.6 µm; mobile phase A: water with 0.03% NH3H2O; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then 0.60 min hold at 95% B; flow rate: 1.2 ml/min. m/z 362.2 [M+H] ⁺ . RT: 0.939 min.

Example 123 Preparation of N-{3-[4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2yl]propyl}benzamide.

Step 1: tert-butyl (3-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinolin-2-yl)-propyl) carbamate.

Cesium carbonate (1.037 d, 3.18 mmol). then tert-butyl (3-bromopropyl) carbamate (0.278 g, 1.17 mmol). The suspension was stirred at room temperature for 40 hours. The reaction mixture was diluted with EtOAc (50 ml) and H ₂ O (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with us. aq. NaCl (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give tert-butyl (3-(4-amino-7-bromo-2H-pyrazolo[3,4-c]quinoline -2-yl) propyl) carbamate (379 mg, 85%) as a white foam. 1H 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, 3H), 4.43 (t, J=7.0 Hz, 2H), 3.01-2.92 (m, 2H), 2.04 (quin, J=6.9 Hz, 2H), 1.37 ( s, 9H). LC-MS m/z 420/422 [M+H] ⁺ .

Step 2. tert-butyl 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)-Spirazole (375 mg, 1.35 mmol) and cesium carbonate (879 mg, 2.70 mmol) was evacuated and refilled with N ₂ , then 1,4-dioxane (8094 µl) and H ₂ O (899 µl) were added. The resulting mixture was purged with N ₂ for 10 min, then [1,H-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (32.9 mg, 0.045 mmol) was added. The mixture was sparged with N ₂ for 1 min, then stirred at 100° C. for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 ml), washed with H2O (100 ml) and

- 74 042018 saturated aqueous NaCl solution (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give t-butyl (3-(4-amino-7-(1-(tetrahydro-2H-pyran-2 )-yl)-1Hpyrazol-5-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)propyl)carbamate (474 mg, quant.) as a brown foam. 1Н NMR (400 MHz, DMSO-d ₆ ) 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]+.

Step 3 2-(3-aminopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA.

To a solution of tert-butyl (3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[3,4-c]quinolin-2 -yl)propyl)carbamate (442 mg, 0.899 mmol) in CH ₂ Cl ₂ (2248 µl) TFA (2248 µl) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (50 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x2 ml) to give 2-(3-aminopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4 α-amine, 2 TFA (423 mg, 88%) as an off-white solid. 1Н NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

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-α-minopropyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-α-min, 2 TFA (40 mg, 0.075 mmol) and benzoic acid (9.1 mg, 0.075 mmol) in DMF (374 μl) at room temperature was added N,N-diisopropylethylamine (52.1 μl, 0.299 mmol) followed by HATU (28.4 mg, 0.075 mmol).

The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 7% B, 7-47% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(3-(4amino-7-(III-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl) propyl)benzamide (10.4 mg, 34%). 1Н 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, 2Н), 3.38-3.31 (m, 2H), 2.26-2.17 (m, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 for 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 412.1 [M+H]+; RT: 1.17 min.

The compounds of examples 124-126 were prepared according to synthetic procedures similar to those described for example 123 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 for 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR

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124 0 уУ ^н M N=< HN^ 413.3 1.01 Ή NMR (400 MHz, METHANOL-d ₄ ) δ 8.65 (s, 1H), 8.43 - 8.37 (m, 1H), 7.97 - 7.96 (m, 1H), 7.95 - 7.93 (m, 1H), 7.91 (d, 7=1.4Hz, 1H), 7.82 - 7.78 (m, 1H), 7.78 -7.75 (m, 1H), 7.71 (d, 7=2.2Hz, 1H), 7.37 (ddd, 7=7.6, 4.8, 1.2Hz , 1H), 6.77 (d, 7=2.2 Hz, 1H), 4.63 (t, 7=6.4 Hz, 2H), 3.59 (t, 7=6.3 Hz, 2H), 2.41 (quin, 7=6.4 Hz, 2H ) 125 O yy ⁿ jjc yy N=< HNy/ 431.1 1.16 Ή NMR (400 MHz, METHANOL-d ₄ ) δ 8.63 (s, 1H), 8.25 (d, 7=2.7 Hz, 1H), 8.00 (dd, 7=8.7, 4.5 Hz, 1H), 7.94 (d, 7 =8.2 Hz, 1H), 7.91 (d, 7=1.2 Hz, 1H), 7.78 - 7.74 (m, 1H), 7.71 (d, 7=2.1 Hz, 1H), 7.54 (td, 7=8.5, 2.8 Hz , 1H), 6.76 (d, 7=2.2 Hz, 1H), 4.63 (t, 7=6.4 Hz, 2H), 3.58 (t, 7=6.3 Hz, 2H), 2.41 (quin, 7=6.3 Hz, 2H ) 126 O H ₂ N N. F ² \__z- NN CH ₃ H N N=< HN^ 350.1 1.03 Ή NMR (500 MHz, DMSOd ₆ ) δ 13.70-12.87 (m, 1H), 9.91-9.08 (m, 2H), 9.00 (s, 1H), 8.15-8.08 (m, 2H), 8.01-7.97 (m, 1H), 7.90 (br d, 7=8.3 Hz, 1H), 7.83 (br s, 1H), 6.79 (s, 1H), 4.53 (brt, 7=6.9 Hz, 2H), 3.11 (q, 7=6.1 Hz, 2H), 2.14-2.07 (m, 2H), 1.82 (s, 3H)

Example 127 Preparation of tert-butyl N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2yl]ethyl}carbamate.

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) were evacuated and refilled with N2, then added 1,4-dioxane (8861 µl) and H2O (985 µl). The resulting mixture was purged with N2 for 10 min, then [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36.0 mg, 0.049 mmol) was added. The mixture was purged with N2 for 1 min, then sealed and stirred at 100°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with H2O (100 mL) and saturated aqueous NaCl (100 mL ), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give tert-butyl (2-(4-amino-7-(thiophen-2-yl)-2H-pyrazolo [3,4-c]quinolin-2yl)ethyl)carbamate (396 mg, 98%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 1.0Hz, 1H), 7.53 (dd, J=5.1, 1.0Hz, 1H), 7.49 (dd, J=8.1, 1.9Hz, 1H), 7.15 (dd, J=5.0, 3.6Hz, 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]+.

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Example 128 Preparation of N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-2methyl-1,3-oxazole -4-carboxamide.

Step 1 2-(2-Aminoethyl)-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA.

To a suspension of tert-butyl (2-(4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2yl)ethyl)carbamate (376 mg, 0.918 mmol) in CH ₂ Cl ₂ (2295 μl) was added with TFA (2295 μl), resulting in the mixture turning into an orange solution (rapid gas evolution noted). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (25 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x10 ml) to give 2-(2-aminoethyl)7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA (428.6 mg, 87%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.95-9.10 (m, 2H), 9.02 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.178.05 (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, 1Н), 7.21 (dd, J=5.1, 3.7 Hz, 1H), 4.76 (t, J=5.7 Hz, 2Н), 3.55-3.48 (m, 2H); LC-MS m/z 310 [M+H]+.

Step 2. N-{2-[4-amino-7-(thiophen-2-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl]ethyl}-2-methyl-1,3oxazol- 4-carboxamide.

To 2-methyloxazole-4-carboxylic acid (13.0 mg, 0.092 mmol) was added N,N-diisopropylethylamine (0.5 M solution in DMF) (0.335 ml, 0.167 mmol) followed by HATU (0.4 M solution in DMF) (0.209 ml, 0.084 mmol). The reaction mixture was stirred at room temperature for 5 min, then it was added dropwise to a suspension of 2-(2-aminoethyl)-7-(thiophen-2-yl)-2H-pyrazolo[3,4c]quinoline-4-amine, 2 TFA (0.25 M in DMF with 0.75 M N,N-diisopropylethylamine (0.335 ml, 0.084 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 µm 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 min hold at 16% B, 16-56% B for 20 min, then 4 min hold at 100% B flow rate: 20 ml/min column temperature: 25° C. Fraction collection was initiated based on MS and UV signals Fractions containing the desired product were pooled and dried by centrifugal evaporation from a floor 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-d ₆ ) 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=6.1Hz, 2H),

3.80 (q, J=5.8 Hz, 2H), 2.42 (s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm), m/z 419 [M+H] ⁺ ; RT: 1.34 min.

Compounds of Examples 129-131 were prepared according to synthetic procedures similar to those described for Example 128 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 for 0.75 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

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Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR 129 ⁿ o ^F n ₂ N__ N . _N N ° ζζ 433.2 1.44 Ή NMR (500 MHz, DMSOd ₆ ) δ 9.02 (brt, 7=5.8 Hz, 1H), 8.68 (s, 1H), 8.59 (d, 7=2.2 Hz, 1H), 8.07 (dd, 7=8.5, 4.4 Hz, 1H), 7.92 7.82 (m, 2H), 7.69 (s, 1H), 7.53 - 7.49 (m, 2H), 7.47 (br d, 7=8.0 Hz, 1H), 7.14 (t, 7=4.3 Hz , 1H), 6.82 - 6.72 (m, 2H), 4.64 (brt,7=5.8Hz, 2H), 3.88 (q, 7=6.1Hz, 2H) 130 h ₂ n ch ₃ WF π n/A ⁰ 352.2 1.2 Ή NMR (400 MHz, METHANOL-d ₄ ) δ 8.73 (s, 1H), 8.08 (d, 7=8.3 Hz, 1H), 7.87 (d, 7=1.6 Hz, 1H), 7.78 (dd, 7=8.2 , 1.7 Hz, 1H), 7.55 (dd, 7=3.6, 1.0 Hz, 1H), 7.49 (dd, 7=5.1,0.9 Hz, 1H), 7.17 (dd, 7=5.1,3.7 Hz, 1H), 4.64 (t, 7=5.9Hz, 2H), 3.79 (t, 7=5.8Hz, 2H), 1.91 (s, 3H) 131 Η ίΠ 415.2 1.42 Ή NMR (500 MHz, DMSOd ₆ ) δ 9.08 - 9.02 (m, 1H), 8.66 (s, 1H), 8.59 (brd,7=3.9 Hz, 1H), 8.01 -7.93 (m, 2H), 7.88 (brd , 7=8.0 Hz, 1H), 7.69 (s, 1H), 7.59 - 7.55 (m, 1H), 7.53 - 7.45 (m, 3H), 7.16-7.11 (m, 1H), 6.84 6.62 (m, 2H) , 4.64 (brt, 7=5.6 Hz, 2H), 3.91 -3.87 (m, 2H)

Example 132 Preparation of N-{2-[4-amino-7-(1H-pyrazol-1-yl)-2H-nurazolo[3,4-c]quinolin-2yl]ethyl}benzamide.

step 3

Step 1: tert-butyl (2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2yl)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) were evacuated and refilled with N2, then DMSO (12.26 ml) was added. The resulting mixture was purged with N2 for 10 min, then N,N'-dimethylethylene diamine (0.396 mL, 3.68 mmol) and copper(I) iodide (0.350 g, 1.84 mmol) were added. The mixture was purged with N2 for 1 min, then sealed and stirred at 120°C for 1 h. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc (200 ml), washed with H2O (200 ml), 1:1 H ₂ O-aq. NH4OH (200 ml) and sat. aq. NaCl (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (80 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give tert-butyl (2(4-amino-7-(1H-pyrazol-1-yl)-2H-nurazolo[ 3,4-c]quinoline-2-yl)ethyl)carbamate (395 mg, 82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 2Н), 6.55-6.53 (m, 1H), 4.46 (br t, J=6.0 Hz, 2Н), 3.49 (q, J=6.0 Hz, 2Н), 1.34 (s, 9H); LC-MS m/z 394 [M+H]+.

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Step 2 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA.

To a solution of tert-butyl (2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin-2yl)ethyl)carbamate (396 mg, 1.01 mmol ) in CH ₂ Cl ₂ (2516 μl) was added TFA (2516 μl) (gas evolution was noted). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (25 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3 x 10 ml) to give 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin- 4-amines, 2 TFA (464 mg, 88%) as white solid. 1Н NMR (400 MHz, DMSO-d ₆ ) δ 9.94-9.69 (m, 1H), 9.529.28 (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]+.

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 mixture was stirred at room temperature for 5 min, then it was added dropwise to a suspension of 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin- 4-amine, 2 TFA (0.25 M in DMF with 0.75 M N,N-diisopropylethylamine) (0.345 mL, 0.086 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 8% B, 8-48% B for 25 min, then 7 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was started based on MS signals. 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[3,4c]quinolin-2-yl) ethyl)benzamide (23.1 mg, 67%). 1H NMR (500 MHz, DMSO-d ₆ ) 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, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 398.1 [M+H]+; RT: 1.24 min.

Example 133 Preparation of N-{2-[4-amino-7-(1H-pyrazol-1-yl)-2H-n-pyrazolo[3,4-c]quinolin-2yl]ethyl}pyridine-2-carboxamide.

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 mixture was stirred at room temperature for 5 min, then it was added dropwise to a suspension of 2-(2-aminoethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[3,4-c]quinolin- 4-amine, 2 TFA (0.25 M in DMF with 0.75 M K,K-diisopropylethylamine) (0.345 ml, 0.086 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ O (0.1 ml) and DMF (to a total volume of 2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 µm; 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 min hold at 8% B, 8-48% B for 23 min, then 6 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. 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-2yl) ethyl)picolinamide (11.4 mg, 33%). 1Н NMR (500 MHz, DMSO-d ₆ ) δ 9.07 (brt, 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 x 50 mm, particles 1.7 µm; 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% in 3

- 79 042018 min, then holding 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 399.0 [M+H]+; RT: 0.98 min.

Example 134 Preparation of methyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo-[4,5-c]quinolin-2yl]methyl] carbamate.

stage 4

Step 1. tert-Butyl N-[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]karbamate.

3-Amino-7-bromoquinolin-4-ol (10 g, 41.83 mmol, 1 eq.), HATU (23.9 g, 62.74 mmol, 1.5 eq.) was added to a 500 ml round bottom flask. , 2-[[(tert-butoxy)-carbonyl]amino]acetic acid (7.3 g, 41.83 mmol, 1 eq.), DCM (100 ml), DIEA (16.2 g, 125.35 mmol , 3.0 eq.). The resulting solution was stirred for 1 hour at room temperature. The resulting solution was washed with 30 ml EtOAc and filtered. The filtrate was concentrated in vacuo. This provided 15 g (90.5%) of tert-butyl N[[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]methyl]carbamate as a pink solid.

Step 2 tert-butyl N-([7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl)carbamate.

To a 500 ml round bottom flask was added tert-butyl N-[[(7-bromo-4-hydroxyquinolin-3yl)carbamoyl]methyl]carbamate (20 g, 50.47 mmol, 1 eq.), THF (250 ml), Lawesson's reagent (16.3 g, 40.38 mmol, 0.8 eq.). The resulting solution was stirred for 3 hours at 70°C. The reaction was then quenched by adding 200 ml aq. _NaHC03 . The mixture was extracted with EtOAc (500 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This provides 9 g (45.2%) of tert-butyl N-([7-bromo-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl)carbamate as a light yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =386.1.

Step 3 7-bromo-2-(((tert-butoxycarbonyl)amino)methyl)thiazolo[4,5-c]quinoline-5-oxide.

tert-Butyl N-([7-bromo-[1,3]-thiazolo[4,5c]quinolin-2-yl]methyl)carbamate (1.3 g, 3.30 mmol, 1 eq.), DCM (20 ml), m-CPBA (3.3 g, 13.19 mmol, 4 eq., 70%). The resulting solution was stirred for 5 hours at room temperature. The residue was applied to a silica gel column with dichloromethane/methanol (70:1). This resulted in 1 g (73.92%) of 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]thiazolo[4,5-c]quinoline-5- um-5-olata as a light yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =412.1.

Step 4: tert-butyl N-[[7-bromo-4-(tert-butylamino)-[1,3]thiazolo[4,5-c]quinolin-2yl]methyl]carbamate.

7-Bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)[1,3]thiazolo[4,5-c]quinoline-5-ium-5-olate ( 700 mg, 1.71 mmol, 1 eq.), DCM (20 ml), 2-methylpropan-2amine (623.9 mg, 8.53 mmol, 5 eq.), (4-methylbenzene)sulfonyl-4-methylbenzene -1-sulfonate (1.1 g, 3.41 mmol, 2 eq.). The resulting solution was stirred for 1 hour at room temperature. Received

- 80 042018 the mixture was concentrated. The crude product was purified by preparative TLC (PE/EA=2:1). This provided 680 mg (85.6%) of tert-butyl N-[[7-bromo-4-(tert-butylamino)-[1,3]thiazolo[4,5c]quinolin-2-yl]methyl]carbamate . as a light yellow solid. LC-MS: (ES, m/z): [M+H]+=466.2.

Step 5. tert-butyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo-[4,5-c]quinolin-2yl]methyl] carbamate.

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

Step 6 Methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2yl]methyl]carbamate.

A solution of tert-butyl N-[[4-(tert-butylamino)-7-(1Hpyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinoline-2- yl]methyl]carbamate (150 mg, 0.33 mmol, 1 eq.) in THF (10 mL). NaH (26.5 mg, 0.66 mmol, 2 eq., 60%) was added followed by methyl carbonochloridate (62.6 mg, 0.66 mmol, 2 eq.). The resulting solution was stirred for 1 hour at room temperature. The reaction was then quenched by adding MeOH. The resulting mixture was concentrated and refluxed in MeOH for 2 h. The reaction mixture was then cooled to room temperature and purified by preparative TLC (EA:PE=1:2). This provided 80 mg (58.80%) of methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5-yl)-[1,3]-thiazolo[4,5-c]quinoline- 2]yl]methyl]carbamate as a light yellow solid. LC-MS: (ES, m/z): [M+H]+=411.1.

Step 7 Methyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl]carbamate.

Methyl N-[[4-(tert-butylamino)-7-(1H-pyrazol-5yl)-[1,3]thiazolo[4,5-c]quinolin]-2-yl] was added to a 25 ml round bottom flask. methyl]carbamate (80 mg, 0.19 mmol, 1 eq) 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 preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 19x250 mm, 10 μm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (10% PhaseB to 60% in 7 min); detector, UV 254 nm. This provided 25.9 mg (37.50%) of methyl N-[[4-amino-7-(1H-pyrazol-5yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl ]methyl]carbamate as a white solid. LC methods: column: Kinetex 2.6 µm EVO C18 100A 3.0x50 mm, 2.6 µm particles; mobile phase A: water-5 mM NH4HCO3; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2.1 minutes, then hold for 0.7 minutes at 95% B; flow rate: 1.2 ml/min. LC-MS: (ES, m/z): [M+H] ⁺ =355.1. ¹ H-NMR: (300 MHz, DMSO-d ₆ , ppm) δ 13.45-12.97 (m, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.897.57 (m, 3H), 7.02 -6.93 (m, 2H), 6.84 (s, 1H), 4.67 (d, J=5.9 Hz, 2H), 3.64 (s, 3H).

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Example 135 Preparation of N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4,5-c]quinolin-2yl)ethyl)benzamide.

Step 1. tert-Butyl N-[2-[(7-bromo-4-hydroxyquinolin-3-yl)carbamoyl]ethyl]carbamate.

Solution of 3-amino-7-bromoquinolin-4-ol hydrochloride (25 g, 90.73 mmol, 1 eq.), 3-[[(tert-butoxy)carbonyl]amino]propanoic acid (20.6 g, 108.87 mmol , 1.20 eq.), HATU (51.7 g, 136.10 mmol, 1.5 eq.) and DIEA (35.2 g, 272.20 mmol, 3 eq.) in DCM (200 ml) were stirred at 25° C. for 3 hours. The resulting mixture was diluted with water (200 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (2x200 ml). The combined organic layers were washed with brine (1x200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was washed with EtOAc (3x100 ml) to give tert-butyl N-[2-[(7bromo-4-hydroxyquinolin-3-yl)carbamoyl]ethyl]carbamate (35 g, 94.02%) as a red solid. LC-MS: (ES, m/z): [M+H]+=410.1.

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 eq) and Lawesson's reagent (3.6 g, 8.90 mmol, 0.99 eq.) in methylbenzene (30 ml) was stirred for 1 h at 100°C. The resulting mixture was diluted with water (100 ml). The mixture was basified to pH 8 with saturated aq. _NaHC03 . The resulting mixture was extracted with EtOAc (3x100 ml). The combined organic layers were washed with brine (1x100 ml), dried over anhydrous Na ₂ SO ₄ 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]quinoline-2- yl]ethyl)carbamate (830 mg, 22.54%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=408.0. ¹ H-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).

Step 3: 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-[1,3]thiazolo[4,5-c]quinoline-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 eq) and m-CPBA (676.2 mg, 3.92 mmol, 2 eq.) in DCM (20 ml) was stirred at room temperature for 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (50:1) to give 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-[1,3]thiazolo[ 4,5-c]quinoline-5-ium-5-olate (432 mg, 51.96%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=424.0.

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[4,5c]quinoline-5-ium-5-olate (2 g , 4.71 mmol, 1 eq.) and NH ₄ OH (10 ml) in DCM (30 ml) was added TsCl (1.8 g, 9.44 mmol, 2.00 eq.). 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 give tert-butyl N-(2-[4-amino-7-bromo-[1,3]thiazolo[4.5c]quinoline- 2-yl]ethyl)carbamate (1.2 g, 60.14%) as a yellow solid. LC-MS: (ES, m/z):

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[M+H]+=423.0. 1H-NMR: ^1H NMR (400 MHz, DMSO-d ₆ ) 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).

Step 5 tert-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2yl]ethyl]carbamate.

To a stirred solution of tert-butyl K-(2-[4-amino-7-bromo-[1,3]thiazolo-[4,5-c]quinolin-2yl]ethyl)carbamate (1.1 g, 2.60 mmol, 1 eq.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-ipyrazole (1.1 g, 5.67 mmol, 2.18 eq. ) and Cs ₂ CO ₃ (2.5 g, 7.80 mmol, 3 eq.) in dioxane (15 ml) and H2O (1.5 ml) was added Pd(dppf)Cl ₂ (0.4 g, 0. 52 mmol, 0.2 eq.) at room temperature under nitrogen. The resulting mixture was stirred for 16 hours at 90° C. under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by preparative TLC (CH ₂ Cl ₂ /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 light yellow solid. LC-MS: (ES, m/z): [M+H]+=411.2.

Step 6 2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinoline-4-amine

tert-Butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)[1,3]thiazolo[4,5-c]quinolin-2-yl] was added to a 25 ml round bottom flask. ethyl]carbamate (80 mg, 0.19 mmol, 1 eq.), DCM (4 ml), HCl in 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 preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (20% phase B to 45% in 8 min); detector, UV 210/254 nm. This provided 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-[1,3]-thiazolo[4,5-c]quinoline-4-amine (15 mg, 24.80% ) as a light yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =311.0. 1H-NMR: 1H NMR (400 MHz, DMSC-d ₆ ) 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).

Step 7 N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4,5-c]quinolin-2-yl)ethyl)benzamide.

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)[1,3]thiazolo[4,5-c]quinoline-4-amine (80 mg, 0. 26 mmol, 1 eq.), DCM (5 ml), TEA (78.2 mg, 0.77 mmol, 3 eq.), benzoyl chloride (43.5 mg, 0.31 mmol, 1.2 eq.). The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: Sunfire Prep C18 OBD column, 10 µm, 19x250 mm; mobile phase, water (0.05% TFA) and CAN (10% phase B to 60% in 7 min); detector, UV 210/254 nm. This provided 15.5 mg (11.38%) of N-(2-(4-amino-7-(1H-pyrazol-5-yl)thiazolo[4.5c]quinolin-2-yl)ethyl)benzamide 2 ,2,2-trifluoroacetate as a light pink solid. LC Methods: Column: Agilent Poroshell HPH-d8 3.0x50 mm, particles 2.7 µm; mobile phase A: water/5 mmol NH ₄ HCO ₃ ; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2.1 minutes, then hold for 0.6 minutes at 95% B; flow rate: 1.0 ml/min. LC RT: 1.236 min. LC-MS: (ES, m/z): [M+H]+=415.2. 1H-NMR: (400 MHz, DMSO-d ₆ , 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).

The compounds of Examples 136-141 were prepared according to synthetic procedures similar to those described in Example 135 from the appropriate starting materials.

Example 136 N-[2-[4-amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]niridine-2carboxamide.

LC Methods: Column: Kinetex EVO 3.0x50 mm, particles 2.6 µm; mobile phase A: water/5 mmol NH ₄ HCO ₃ ; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1.2 ml/min. LC RT: 1.207 min. LC-MS: (ES, m/z): [M+H]+=416.0. 1H-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).

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Example 137 N-[2-[4-Amino-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]ethyl]oxetan-2carboxamide.

LC methods: column: Express C18 2.1x50 mm, particles 2.7 µm; mobile phase A: water + 0.05% TFA; mobile phase B: acetonitrile + 0.05% TFA; temperature: 40°C; gradient: 5 to 100% B over 2 min, then hold 0.7 min at 100% B; flow rate: 1.0 ml/min. LCRT: 0.829 min. LCMS: (ES, m/z): [M+H] ⁺ =395.1. ¹ H-NMR: (400 MHz, DMSO-d ₆ , 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).

Example 138 2-(3-aminopropyl)-7-(1H-pyrazol-5-yl)-1,3]thiazolo[4,5-c]quinoline-4-amine

^ ⁿ 2 NH ₂ | G y __ /

LC Methods: Column: Shim-pack XR-ODS, 3.0x50 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 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1.5 ml/min. LCRT: 0.776 min. LC-MS: (ES, m/z): [M+H]+=325.3. 1Н NMR: (400 MHz, Methanol-d ₄ , 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).

Example 139 N-[3-[4-amino-7-(1H-nirazol-5-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]propyl]α-cetamide.

NH ₂ __\

N JJ ^S “Η ⁰ _N Qf ^SNz

LC Methods: Column: Kinetex EVO, 3.0x50 mm, particles 2.6 µm; mobile phase A: water with 10 mM NH4HCO3; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; 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-d ₆ , 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).

Example 140 N-{[4-Amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]methyl}-N-ethylacetamide.

LC Methods: Column: Shim-pack XR-ODS, 3.0x50 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 to 50% B in 2 min, 50 to 100% B in 0.3 min, then hold 0.4 min at 100% B; flow rate: 1.2 ml/min. LC RT: 1.679 min. LC-MS: (ES, m/z): [M+H]+=367.1. 1H-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).

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Example 141 2-[3-(Benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinoline-4-amine

1H NMR (400 MHz, methanol-d ₄ ) 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.

Example 142 Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4,5-c]quinolin-2-yl]propan-1ol.

A solution of 2-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3yl)-[1,3]thiazolo[4,5-c]quinoline-4-amine (290 mg , 0.70 mmol, 1.00 eq.) in ethanol (30 ml). Pd(OH) ₂ (29 mg) was added to the solution. The resulting solution was degassed and refilled with hydrogen. The resulting solution was stirred for 2 hours at 80° C. in an oil bath. Solids were collected by filtration. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions (HPLC-10): XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH4HCO ₃ ) and ACN (10.0% ACN to 36.0% in 8 min); detector, 254/210 nm. This provided 35.7 mg (16%) of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]thiazolo[4.5c]quinolin-2-yl]propan-1 -ol as a white solid. LC-MS: (ES, m/z): [M+H] ⁺ =326.0. 1HNMR: (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).

Example 143 Preparation of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinoline4-amine

2-(Aminomethyl)-7-(1H-pyrazol-5-yl)[1,3]thiazolo[4,5-c]quinoline-4-amine (50 mg, 0.17 mmol , 1 eq.), MeOH (5 ml), AcOH (0.1 ml), HCHO (41.1 mg, 0.51 mmol, 3.00 eq., 37%), NaBH ₄ (19.1 mg, 0.51 mmol, 3.00 eq.). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH4HCO3) and ACN (20% phase B to 60% in 8 min); detector, UV 254 nm. This provided 10.1 mg (18.45%) of 2-[(dimethylamino)methyl]-7-(1Hpyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinoline-4-amine as a white solid. LC Methods: Column: Kinetex EVO C18 3.0x50 mm, particles 2.6 µm; mobile phase A: water/5 mmol NH4HCO3; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1.2 ml/min. LCRT: 0.81 min. LC-MS: (ES, m/z): [M+H] ⁺ =325.0. ¹ H-NMR: (400 MHz, DMSO-d ₆ , 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).

Example 144 Preparation of 2-[3-(diethylamino)propyl]-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5c]quinoline-4-amine

2-(3-Aminopropyl)-7-(1H-pyrazol-5-yl)-[1,3]thiazolo[4,5-c]quinoline-4-amine solution (70 mg, 0.22

- 85 042018 mmol, 1 eq.), acetaldehyde (14.3 mg, 0.32 mmol, 1.5 eq.) and NaBH ₃ CN (27.1 mg, 0.43 mmol, 2 eq.) in CH ₃ COOH (0.5 ml) and MeOH (10 ml) were stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18, 30x150 mm 5 µm column; mobile phase A: water (10 mM NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 ml/min ; gradient: 25 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]quinoline-4-amine (9.8 mg, 11.94%) as an off-white solid. LC Methods: Column: Shim-pack XR-ODS 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 95% B over 1.7 min, then hold for 1.0 min at 95% B; flow rate: 1.5 ml/min. LCRT: 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).

Example 145 c] quinoline-4-amine.

Preparation of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-

Step 1 tert-butyl N-([7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate.

To a 500 ml round bottom flask was added tert-butyl N-[[(7-bromo-4-hydroxyquinolin-3yl)carbamoyl]methyl]carbamate (10 g, 25.24 mmol, 1 eq.), DCM (250 ml), CCl ₃ CCl ₃ (9.0 g, 37.86 mmol, 1.50 eq.), TEA (10.2 g, 100.80 mmol, 3.99 eq.), PPh ₃ (9.9 g, 37 .75 mmol, 1.50 eq.). 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 3x200 ml, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:4) to give 5 g (52.38%) tert-butyl N-([7-6pom[1.3]oxazolo[4.5-c] quinolin-2-yl]methyl)carbamate as a pink solid. LC-MS: (ES, m/z): [M+H] ⁺ =378.0.

Step 2. 7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)-[1,3]oxazolo[4,5-c]quinoline-5-ium-5olate.

In a 100 ml round bottom flask was placed tert-butyl N-([7-bromo-[1,3]oxazolo[4,5c]quinolin-2-yl]methyl)carbamate (4.2 g, 11.10 mmol, 1 eq.), DCM (50 ml), m-CPBA (9.6 g, 55.63 mmol, 5.01 eq.). The resulting solution was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column using 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]quinoline- 5-ium-5-olata as a yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =394.0.

Step 3 tert-butyl N-([4-amino-7-bromo-[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate.

7-bromo-2-([[(tert-butoxy)carbonyl]amino]methyl)- 86 042018

[1,3]oxazolo[4,5-c]quinoline-5-ium-5-olate (1.8 g, 4.57 mmol, 1 eq.) in DCM (5 ml) and NH3H2O (5 ml). TsCl (1.8 g, 9.44 mmol, 2.07 eq.) was then added. The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane/methanol (50:1). The resulting mixture was concentrated under vacuum. This provided 950 mg (52.91%) of tert-butyl K-([4-amino-7bromo[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl)carbamate as an orange solid . LC-MS: (ES, m/z): [M+H]+=393.0.

Step 4 tert-butyl N-[[4-amino-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinolin-2yl]methyl]carbamate.

tert-Butyl N-([4-amino-7-bromo-[1,3]oxazolo[4,5c]quinolin-2-yl]methyl)carbamate (900 mg, 2.29 mmol , 1 eq.), 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2yl)-1H-pyrazole (0.9 g, 4.58 mmol, 2.00 eq.) , Cs ₂ CO ₃ (2.2 g, 6.87 mmol, 3.00 eq.) and Pd(dppf)Cl ₂ (334.9 mg, 0.46 mmol, 0.20 eq.) in dioxane (5 ml) and H2O (0.5 ml) under N2 atmosphere. The resulting mixture was stirred overnight at 105° C. under nitrogen. The resulting mixture was concentrated in vacuo. The residue was purified on a silica gel column using ethyl acetate/petroleum ether (1:4) to give 680 mg (78.10%) tert-butyl N-[[4-amino-7-(1H-pyrazol-5-yl) -[1,3]oxazolo[4,5-c]quinolin-2yl]methyl]carbamate as a brown solid. LC-MS: (ES, m/z): [M+H] ⁺ =381.2.

Step 5 2-(Aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinoline-4-amine

tert-Butyl N-[[4-amino-7-(1H-pyrazol-5-yl)[1,3]oxazolo[4,5-c]quinolin-2-yl]methyl] was added to a 25 ml round bottom flask. carbamate (100 mg, 0.26 mmol, 1 eq.) in DCM (5 ml) and HCl (4N) in dioxane (2 ml). The resulting solution was stirred for 1.5 hours at room temperature. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC using the following conditions: XBridge Shield RP18 OBD column, 5 µm, 19x150 mm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (15% phase B to 33% in 8 min); detector, UV 254 nm. This provided 8.9 mg (12.08%) of 2-(aminomethyl)-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinoline-4amine as a yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ = 281.1. 1H-NMR: 1H 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).

Step 6 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)-[1,3]oxazolo[4,5-c]quinoline-4-amine

2-(Aminomethyl)-7-(1H-pyrazol-5-yl)[1,3]oxazolo[4,5-c]quinoline-4-amine (40 mg, 0.14 mmol , 1 eq.), HCHO (12.9 mg, 0.43 mmol, 3.0 eq.) in MeOH (2 ml) and CH3COOH (0.2 ml). NaBH ₃ CN (26.9 mg, 0.43 mmol, 3.0 eq.) was then added. The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated. The crude product was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18, 30x150 mm, 5 µm; mobile phase A: water (10 mM NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 5 to 40% B in 7.5 minutes; 254/210 nm; RT: 7.1 min. This provided 10 mg (22.73%) of 2-[(dimethylamino)methyl]-7-(1H-pyrazol-5-yl)[1,3]oxazolo[4,5-c]quinoline-4-amine in form of a white solid. LC Methods: Column: Kinetex EVO C18 3.0x50 mm, particles 2.6 µm; mobile phase A: water/5 mmol NH ₄ HCO ₃ ; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1.2 ml/min. LC RT: 1.039 min. LC-MS: (ES, m/z): [M+H] ⁺ =309.1. ¹ H-NMR: (300 MHz, CD ₃ OD, ppm) δ 8.16-7.98 (m, 2H), 7.82 (d, J=37.3 Hz, 2H), 6.81 (s, 1H), 3.98 (s, 2H) , 2.48(s, 6H).

Example 146 2-[3-(Benzyloxy)propyl]-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinoline-4-amine

Example 146 was prepared according to synthetic procedures similar to those described in Example 145 using the appropriate starting materials. 1H NMR (400 MHz, methanol-d4) δ 8.02 (br s, 1H), 7.97 (d, J=8.3 Hz, 1H), 7.64 (br d, J=1.5 Hz, 1H), 7.53 (s, 1H) , 7.31-7.16 (m, 5H), 6.74 (d, J=1.6 Hz, 1H), 4.51 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 3.17 (t, J=7.3 Hz, 2H), 2.33 - 2.18 (m, 2H). LC-MS: (ES, m/z): [M+H] ⁺ =400.2.

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Example 147 Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]propan1-ol

A solution of 2-[3-(benzyloxy)-propyl]-7-(1H-pyrazol3-yl)-[1,3]oxazolo[4,5-c]quinoline-4-amine (200 mg, 0.50 mmol, 1.00 eq.) in ethanol (30 ml). Pd(OH) ₂ (100 mg) was added to the solution. The resulting solution was degassed and refilled with hydrogen. The resulting solution was stirred for 2 days at 70° C. in an oil bath. Solids were removed by filtration. The solution was concentrated under vacuum. The residue was purified by preparative HPLC using the following conditions (HPLC-10): X Bridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH ₄ HCO ₃ ) and ACN (10.0% ACN to 36.0% in 8 min); detector, UV 254/210 nm. This provided 45 mg (29%) of 3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinolin2-yl]propan-1-ol as a white solid. LC-MS: (ES, m/z): [M+H]+=310.1. ¹ H-NMR: (CD ₃ OD, 300 MHz, ppm): δ 8.14-7.96 (m, 2H), 7.85-7.81 (m, 1H), 7.78-7.68 (m, 1H), 6.79 (s, 1H) , 3.74 (t, J=6.0 Hz, 2H), 3.17 (t, J=4.5 Hz, 2H), 2.21-2.12 (m, 2H).

Example 148 Preparation of 3-[4-amino-7-(1H-pyrazol-3-yl)furo[2,3-c]quinolin-2-yl]propan-1-ol

Stage 1. 7-bromo-4-iodoquinoline-3-ol.

A solution of 7-bromoquinolin-3-ol (2000 mg, 8.93 mmol, 1.00 eq.) in 2N NaOH solution (40 ml) was placed in a 250 ml round bottom flask. To this mixture was added dropwise a solution of iodine (4536 mg, 17.86 mmol) in 20% aqueous potassium iodide (40 ml). The resulting solution was stirred for 3 hours at 25°C. Then the pH value of the solution was adjusted to 6-7 with acetic acid. The solids were collected by filtration and washed three times with 15 ml H2O. This provided 2740 mg (88%) of 7-bromo-4-iodoquinolin-3-ol as a yellow solid. LC-MS: (ES, m/z): [M+H]+=350.0.

Step 2 3-[7-bromofuro[2,3-c]quinolin-2-yl]propan-1-ol.

To a 250 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added a solution of 7-bromo-4-iodoquinolin-3-ol (1575 mg, 4.50 mmol, 1.00 eq.) in CH ₃ CN (20 ml ) and TEA (10 ml). To the solution were added pent-4-yn-1-ol (378 mg, 4.50 mmol, 1.00 eq.), Pd(PPh ₃ ) ₄ (156 mg, 0.14 mmol, 0.03 eq.) and CuI (27 mg, 0.14 mmol, 0.03 eq). The resulting solution was stirred for 12 hours at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1/2). This provided 681 mg (49%) of 3-[7-bromofuro[2,3-c]quinolin-2-yl]propan-1-ol as a yellow solid LC-MS: (ES, m/z): [M+H]+=306.2.

Step 3: 7-bromo-2-(3-hydroxypropyl)furo[2,3-c]quinoline-5-ium-5-olate.

To a 250 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added a solution of 3-[7-bromofuro[2,3-c]quinolin-2-yl]-propan-1-ol (681 mg, 2.22 mmol , 1.00 equiv.) in di

- 88 042018 chloromethane (20 ml). m-CPBA (824 mg, 4.77 mmol, 2.15 eq) was added to the solution. The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column using dichloromethane/methanol (25/1). This provided 470 mg (66%) of 7-bromo-2-(3-hydroxypropyl)furo[2,3-c]quinoline-5-ium-5-olate as a yellow solid. LC-MS: (ES, m/z): [M+H]+=322.2.

Step 4. 3-[4-Amino-7-bromofuro[2,3-c]quinolin-2-yl]propan-1-ol A solution of 7-bromo-2-(3-hydroxypropyl) was added to a 250 ml round bottom flask. furo[2,3-c]quinoline-5-ium-5-olate (470 mg, 1.46 mmol, 1.00 eq.) in dichloromethane (20 mL). NH3-H2O (10 ml) and TsCl (416 mg, 2.18 mmol, 1.50 eq.) were added to the solution. The resulting solution was stirred for 2 hours at 25°C. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column using dichloromethane/methanol (10/1). This provided 390 mg (83%) of 3-[4-amino-7-bromofuro[2,3c]quinolin-2-yl]propan-1-ol as a yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =321.2.

Step 5 3-[4-Amino-7-(1H-pyrazol-3-yl)furo[2,3-c]quinolin-2-yl]propan-1-ol.

A 100 ml round-bottom flask, purged and maintained under an inert nitrogen atmosphere, was filled with a solution of 3-[4-amino-7-bromofuro[2,3-c]quinolin-2-yl]propan-1-ol (390 mg, 1 .21 mmol, 1.00 eq.) in dioxane/water (15/3 mL). To the solution was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (350 mg, 1.80 mmol, 1.49 eq.), Cs ₂ CO ₃ (785 mg, 2.45 mmol , 2.01 eq.) and Pd(dppf)Cl ₂ .DCM (200 mg, 0.24 mmol, 0.20 eq.). The resulting solution was stirred for 12 hours at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was loaded onto a silica gel column using dichloromethane/methanol (10/1). The resulting crude product (250 mg) was purified by preparative HPLC using the following conditions (HPLC-10): XBridge Shield RP18 OBD column, 19x250 mm, 10 µm; mobile phase, water (10 mM NH4HCO3) and ACN (15.0% ACN to 35.0% in 9 min); detector, UV 254/210 nm. This provided 77 mg (21%) of 3-[4-amino-7-(1H-pyrazol-3yl)furo[2,3-c]quinolin-2-yl]propan-1-ol as a white solid. LC-MS: (ES, m/z): [M+H] ⁺ =309.1. 1H-NMR (CD3OD, 400 MHz, ppm): δ 8.10-8.01 (m, 2H), 7.86-7.64 (m, 2H), 7.10 (s, 1H), 6.77 (s, 1H), 3.69 (t, J =6.4 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.09-2.02 (m, 2H).

Example 149 Preparation of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-p-pyrazolo[4,3-c]quinoline-4-amine

Step 1. 7-bromo-2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.

The carbonate potassium (402 mg, 2.91 mmol) and 1(chloromethyl)-4-methoxybenzene (158 µl, 1.163 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with 10% MeOH-EtOAc (200 ml), washed with H2O (200 ml) and saturated aqueous NaCl (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Used without further purification. LC-MS m/z 384/386 [M+H] ⁺ . Apparently, there was a small amount of regioisomeric product, and was used in the next three stages of the synthesis.

- 89 042018

Step 2. 7-bromo-4-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]quinoline.

To a mixture of 7-bromo-2-(4-methoxybenzyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (crude product from previous reaction) in CH ₂ Cl ₂ (4548 µl ) and DMF (227 μl) at 0°C was added dropwise phosphoryl chloride (107 μl, 1.146 mmol). The solution was stirred at room temperature for 17 hours. Additional POCl ₃ (53.5 μl) was added and stirred at room temperature for 1.5 hours. Additional DMF (0.5 ml) was added and stirred for 3 hours. The reaction was quenched by slow addition with stirring of 1.5 M aq. K2HPO4 (100 ml). The mixture was extracted with CH ₂ Cl ₂ (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in a mixture of CH ₂ Cl ₂ and Meon, mixed with celite and concentrated in vacuo. This material was loaded onto the column by dry injection and repurified by flash chromatography (40 g silica gel; linear gradient 0-100% EtOAc-CH ₂ Cl ₂ ) to give 7-bromo-4-chloro-2-(4-methoxybenzyl)- 2H-pyrazolo[4,3-c]quinoline (108 mg, 28%) as an off-white solid. LC-MS m/z 402/404 [M+H]+.

Step 3. 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[4,3-c]quinoline-4-amine.

To a solution of 7-bromo-4-chloro-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-c]quinoline (108 mg, 0.268 mmol) in DMSO (894 µl) was added (4-methoxyphenyl )methanamine (70.1 µl, 0.536 mmol) and N,N-diisopropylethylamine (140 µl, 0.805 mmol). The reaction mixture was stirred at 80° C. for 22 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H ₂ O (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. This product was used without further purification. LC-MS m/z 503/505 [M+H] ⁺ .

Step 4. 7-bromo-2H-pyrazolo[4,3-c]quinoline-4-amine, TFA.

A solution of 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[4,3-c]quinoline-4-amine (143 mg, 0.284 mmol) in TFA (568 µl) was sealed and stirred at 70 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was concentrated from CH ₂ Cl ₂ (2x2 ml). The crude product was mixed with CH ₂ Cl ₂ (0.5 ml), filtered and washed with CH ₂ Cl ₂ (3x0.5 ml) to obtain 7-bromo-2H-pyrazolo[4,3-c]quinoline-4-amine, TFA (99 mg, 92%) as a white solid. LC-MS m/z 263/265 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.26-12.95 (m, 1H), 9.81-9.57 (m, 1H), 8.95-8.56 (m, 2H), 8.18 (d, J=8.5 Hz, 1H) , 7.93 (br s, 1H), 7.80–7.70 (m, 1H).

Step 5 tert-Butyl (2-(4-amino-7-bromo-2H-pyrazolo[4,3-c]quinolin-2-yl)ethyl)carbamate

Cesium carbonate (254 mg, 0.780 mmol ) followed by tert-butyl (2-bromoethyl)carbamate (64.1 mg, 0.286 mmol). The suspension was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (20 ml) and H ₂ O (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ and filtered. Celite was added and the mixture concentrated in vacuo. This material was loaded onto a dry-load column and purified by flash chromatography (24 g silica gel with 5 g dry-load cartridge; linear gradient 0-10% MeOHCH2Cl2) to give t-butyl (2-(4-amino-7- bromine-2H-pyrazolo[4,3-c]quinolin-2-yl)ethyl)carbamate (54.2 mg, 51%). The product was consistent with the second of two observed regioisomeric peaks eluted from the column; it was a less polar product observed under LC-MS conditions. LC-MS m/z 406/408 [M+H]+; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.42 (s, 1H), 7.98 (d, J=8.3 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.29 (dd, J= 8.3, 2.0 Hz, 1H), 7.16-7.06 (m, 2H), 6.99 (br t, J=5.6 Hz, 1H), 4.43 (br t, J=5.9 Hz, 2H), 3.43 (q, J=5.9 Hz, 2H), 1.33 (s, 9H).

Step 6. tert-butyl 2-yl)ethyl)carbamate.

A mixture of tert-butyl (2-(4-amino-7-bromo-2H-pyrazolo[4,3-c]quinolin-2-yl)ethyl)carbamate (53.2 mg, 0.131 mmol), 1-(tetrahydro- 2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (54.6 mg, 0.196 mmol) and cesium carbonate (128 mg, 0.393 mmol) was evacuated and refilled with N2, then 1,4-dioxane (1178 µl) and H2O (131 µl) were added. The resulting mixture was purged with N2 for 15 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (4.79 mg, 6.55 µmol) was added. The mixture was purged with N2 for 1 min, then stirred at 100°C for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H2O (20 ml) and saturated aqueous NaCl (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; 010% MeOH-CH ₂ Cl ₂ linear gradient) to give t-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2)- yl)-1H-pyrazol5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)ethyl)carbamate. LC-MS m/z 478 [M+H] ⁺ .

Step 7 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine

To a solution of tert-butyl (2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[4,3-c]quinoline-2 -yl)ethyl)carbamate (62.6 mg, 0.131 mmol) in CH ₂ Cl ₂ (328 μl) TFA was added

- 90 042018 (328 µl). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (4 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x1 ml) to give 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4 α-amine, 2 TFA (64.3 mg, 94%) as a white solid. A portion of this product (10 mg) was further purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 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-minute hold at 0% B, 0-40% B for 20 minutes, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine, 2 TFA (7.1 mg). 1Н NMR (500 MHz, DMSO-d6) δ 13.24-13.03 (m, 1H), 9.52-8.98 (m, 1H), 8.90 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 8.09 ( br s, 1H), 7.92 (br d, J=5.9 Hz, 1H), 7.88 - 7.78 (m, 1H), 6.82 (d, J=2.1 Hz, 1H), 4.73 (br t, J=5.6 Hz, 2H), 3.48-3.44 (m, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 294.0 [M+H]+; RT: 0.52 min.

Example 150 Preparation of N-{2-[4-α-mino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2yl]ethyl}pyridine-2-carboxamide.

To a solution of picolinic acid (7.06 mg, 0.057 mmol) in DMF (174 µl) was added N,N-diisopropylethylamine (18.17 µl, 0.104 mmol) at room temperature, followed by HATU (19.84 mg, 0.052 mmol) . This mixture was stirred at room temperature for 5 minutes, then it was added dropwise to a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin- 4-amine, 2 TFA (27.2 mg, 0.052 mmol) and N,N-diisopropylethylamine (27.3 µl, 0.157 mmol) in DMFA (174 µl). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H ₂ O (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, 200x19 mm, particles 5 μm; 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 min hold at 4% B, 4-44% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1Hpyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl) ethyl)picolinamide (14.2 mg, 68%). 'll NMR (500 MHz, DMSO-d ₆ ) δ 9.10 (t, J=5.9 Hz, 1H), 8.62 (d, J=4.7 Hz, 1H), 8.46 (s, 1H), 8.08 (d, J= 8.1 Hz, 1H), 8.03-7.95 (m, 2H), 7.87 (d, J=1.3 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.61-7.57 ( m, 1H), 7.07-6.84 (m, 2H), 6.75 (d, J=2.1 Hz, 1H), 4.63 (t, J=6.0 Hz, 2H), 3.86 (q, J=5.9 Hz, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 399. [M+H]+; RT: 0.92 min.

Example 151 Preparation of N-{2-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl]ethyl}2-chloro-1, 3-thiazole-4-carboxamide.

To a solution of 2-chlorothiazole-4-carboxylic acid (9.39 mg, 0.057 mmol) in DMF (130 µl) at room temperature was added N,N-diisopropylethylamine (18.17 µl, 0.104 mmol) followed by HATU (19, 84

- 91 042018 mg, 0.052 mmol). This mixture was stirred at room temperature for 5 minutes, then it was added dropwise to a solution of 2-(2-aminoethyl)-7-(III-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin- 4-amine, 2 TFA (27.2 mg, 0.052 mmol) and K,K-diisopropylethylamine (27.3 µl, 0.157 mmol) in DMF (130 µl). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 7% B, 7-47% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-7-(1Hpyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl) ethyl)-2-chlorothiazole-4-carboxamide (14.7 mg, 64%). 1Н NMR (500 MHz, DMSO-d ₆ ) δ 8.83 (br t, J=5.5 Hz, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.09 (d, J=8.3 Hz, 1H) , 7.87 (s, 1H), 7.71 (br s, 1H), 7.63 (br d, J=7.7 Hz, 1H), 6.99-6.88 (m, 2H), 6.76 (d, J=1.9 Hz, 1H), 4.60 (br t, J=5.6 Hz, 2H), 3.82-3.75 (m, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 439.0 [M+H]+; RT: 1.16 min.

Example 152 Preparation of 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine

Stage 1. Synthesis of 7-bromoquinoline-4-amine.

A solution of 7-bromo-4-chloroquinoline (6.8 g, 28.04 mmol, 1 eq.) in aqueous ammonia (20 ml) and CH3CN (50 ml) was stirred for 2 days at 120°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 7-bromoquinoline-4-amine (1.1 g, 17.59%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=223.0/225.0.

Stage 2. Synthesis of 7-bromo-3-iodoquinoline-4-amine.

A solution of 7-bromoquinoline-4-amine (1.1 g, 4.93 mmol, 1 eq.) and NIS (1029 mg, 5.92 mmol, 1.2 eq.) in CH3CN (20 mL) was stirred for 2 h at 65°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 7-bromo-3-iodoquinoline-4-amine (850 mg, 49%) as a brown-yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =249.9/251.9. ¹ H NMR (400 MHz, DMSO-de) δ 8.63 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 7.96 (d, J=1.7 Hz, 1H), 7.60 (dd, J=9.0 , 1.7 Hz, 1H), 7.01 (s, 2H).

Stage 3. Synthesis of tert-butyl K-[4-(4-amino-7-bromoquinolin-3-yl)but-3-yn-1-yl]carbamate.

7-bromo-3-iodoquinoline-4-amine solution (3 g, 8.6 mmol, 1 eq.), tert-butyl K-(but-3-yn-1

- 92 042018 yl) carbamate (1745 mg, 10.3 mmol, 1.2 eq.), CuI (163.7 mg, 0.86 mmol, 0.1 eq.), Pd (PPh ₃ ) ₂ Cl ₂ ( 603.4 mg, 0.86 mmol, 0.1 eq.) and TEA (4349 mg, 42.9 mmol, 5 eq.) in Et ₂ O (30 ml) were stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give tert-butyl N-[4-(4-amino-7-bromoquinolin-3-yl)but-3-yn-1-yl ]carbamate (1.4 g, 41.7%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=390.1/392.1.

Step 4. Synthesis of tert-butyl N-(2-[7-bromo-1H-pyrrolo[3,2-c]quinolin-2-yl]ethyl)carbamate.

A solution of tert-butyl N-[4-(4-amino-7-bromoquinolin-3-yl)but-3-yn-1-yl]-carbamate (1.8 g, 4.612 mmol, 1 eq.) and KOH ( 5.17 g, 9.2 mmol, 2.0 eq.) in DMF (20 ml) was stirred overnight at 40° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give t-butyl N(2-[7-bromo-1H-pyrrolo[3,2-c]quinolin-2-yl]ethyl) carbamate (540 mg, 30%) as a yellow solid. LC-MS (ES, m/z): [M+H] ⁺ =390.1/392.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 9.02 (s, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H) , 7.74 (dd, J=8.8, 1.8 Hz, 1H), 7.04 (t, J=5.5 Hz, 1H), 6.54 (s, 1H), 3.39-3.35 (m, 2H), 2.96 (t, J=7.2 Hz, 2H), 1.37 (s, 9H).

Step 5. Synthesis of 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-1H-pyrrolo[3,2-c]quinoline-5ium-5-olate.

A solution of tert-butyl N-(2-[7-bromo-1H-pyrrolo[3,2-c]quinolin-2-yl]ethyl)-carbamate (360 mg, 0.922 mmol, 1 eq) and mCPBA (318, 3 mg 1.85 mmol, 2 eq.) in DCM (10 ml) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (20:1) to give 7-bromo-2-(2[[(tert-butoxy)carbonyl]amino]ethyl)-1H-pyrrolo[3 ,2-c]quinoline-5-ium-5-olate (120 mg, 32%) as yellow solid LC-MS (ES, m/z): [M+H]+=406.1/408.1.

Step 6. Synthesis of tert-butyl N-(2-[4-amino-7-bromo-1H-pyrrolo[3,2-c]quinolin-2-yl]ethyl)carbanate.

A solution of 7-bromo-2-(2-[[(tert-butoxy)carbonyl]amino]ethyl)-1H-pyrrolo[3,2-c]quinoline-5-ium-5olate (180 mg, 0.44 mmol, 1 eq.) and TsCl (168.9 mg, 0.88 mmol, 2 eq.) in NH3H2O (5 ml) and DCM (15 ml) were stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (30:1) to give tert-butyl N-(2-[4-amino-7-bromo-1H-pyrrolo[3,2-c] quinolin-2yl]ethyl)carbamate (175 mg, 97.5%) as a yellow solid. LC-MS (ES, m/z): [M+H] ⁺ =405.1/407.1.

Step 7. Synthesis of tert-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-1H-pyrrolo-[3,2-c]quinolin-2yl]ethyl]carbamate.

A solution of tert-butyl N-(2-[4-amino-7-bromo-1H-pyrrolo[3,2-c]quinolin-2-yl]ethyl)-carbamate (175 mg, 0.43 mmol, 1 eq. ), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)--4H-pyrazole (167.6 mg, 0.86 mmol, 2.0 eq.), Pd(dppf)Cl ₂ (63.19 mg, 0.086 mmol, 0.2 eq.) and Cs ₂ CO ₃ (422 mg, 1.295 mmol, 3 eq.) in dioxane (10 ml) and H2O (1 ml) were stirred overnight at 90° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (10:1) to give t-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-1H-pyrrolo[ 3,2-c]quinolin-2-yl]ethyl]carbamate (152 mg, 89.7%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=393.2.

Step 8. Synthesis of 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine.

A solution of tert-butyl N-[2-[4-amino-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinolin-2yl]ethyl]carbamate (152 mg, 0.38 mmol, 1 eq.) in HCl in 1,4-dioxane (4N, 5 ml) was stirred for 2 h at room temperature. The resulting mixture was concentrated in vacuo and then purified by preparative HPLC using the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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: 1 minute hold at 0% B, 0-40% B for 20 minutes, then 4 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was started based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. LC-MS: (ES, m/z): [M+H]+=293.0. 1Н NMR (500 MHz, DMSO-d6) δ 8.94-8.55 (m, 1H), 8.23 (br d, J=8.2 Hz, 1H), 8.17 (br d, J=0.8 Hz, 1H), 7.97 (br d , J=7.2 Hz, 1H), 7.92-7.81 (m, 1H), 6.94 (s, 1H), 6.84 (br s, 1H), 3.42-3.42 (m, 1H), 3.29-3.19 (m, 2H) , 3.14 (br d, J=7.6 Hz, 2H).

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Example 153 Preparation of 2-[2-(dimethylamino)ethyl]-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline4-amine

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine solution (50 mg, 0.17 mmol, 1 eq.), HCHO (15.4 mg, 0.51 mmol, 3 eq.) and NaBH ₃ CN (21.5 mg, 0.34 mmol, 2 eq.) in MeOH (10 ml) and CH3COOH (0.5 ml) were stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Sunfire Prep C18 OBD, 10 µm, 19x250 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 15 to 30% B over 8 min; 254/210 nm; Rt: 6.37 min) to give 2-[2-(dimethylamino)ethyl]-7-(1H-pyrazol-5-yl)-1Hpyrrolo [3,2-c]quinoline-4-amine; bis(trifluoroacetic acid) (13.4 mg, 14.29%) as an off-white solid. LC-MS: (ES, m/z): [M+H]+ =321.2 1H NMR (400 MHz, methanol-d ₄ , ppm) δ 8.17 (dd, J=8.5, 2.5 Hz, 1H), 8.06 ( dt, J=3.7, 1.8Hz, 1H), 7.95 (dt, J=8.3, 1.6Hz, 1H), 7.77 (d, J=2.3Hz, 1H), 6.92 (d, J=2.5Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 3.60 (dd, J=8.9, 6.8 Hz, 2H), 3.36 (t, J=7.9 Hz, 2H), 3.01 (s, 6H).

Example 154 Preparation of N-{2-[4-amino-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinolin-2yl]ethyl}propanamide.

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine solution (50 mg, 0.17 mmol, 1 eq.), propanoyl chloride (19.0 mg, 0.21 mmol, 1.2 eq.) and TEA (34.6 mg, 0.34 mmol, 2 eq.) in DCM (10 ml) were stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions (column: Sunfire Prep C18 OBD, 10 µm, 19x250 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 15 to 30% B over 8 min; 254/210 nm; RT: 6.37 min) to give 3,3,3-trifluoroprop-1-en-2-ol N-[2-[4-amino -7-(1H-pyrazol-5-yl)-1Hpyrrolo[3,2-c]quinolin-2-yl]ethyl]propanamide hydrate (8.5 mg, 10.39%) as an off-white solid. LC-MS (ES, m/z): [M+H] ⁺ =349.2. 1Н NMR (400 MHz, methanol-d ₄ , ppm) δ 8.16 (d, J=8.4 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.94 (dd, J=8.4, 1.6 Hz, 1H ), 7.76 (d, J=2.3 Hz, 1H), 6.83-6.80 (m, 2H), 3.59 (t, J=7.1 Hz, 2H), 3.05 (t, J=7.0 Hz, 2H), 2.20-2.18 (m, 2H), 1.10 (t, J=7.6 Hz, 3H).

Example 155 Preparation of N-[2-[4-amino-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinolin-2yl]ethyl]pyridine-2-carboxamide.

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine solution (50 mg, 0.17 mmol, 1 eq.), pyridine-2-carboxylic acid (25.2 mg, 0.21 mmol, 1.2 eq.), HATU (130 mg, 0.34 mmol, 2 eq.) and DIEA (66.3 mg, 0.51 mmol , 3 eq.) in DCM (10 ml) was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC using the following conditions (column: Sunfire Prep C18 OBD, 10 µm, 19x250 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 ml/min; gradient: 15 to 40% B over 8 min; 254/210 nm; RT: 7.5 min) to give N-[2-[4-amino-7-(1H-pyrazol5-yl)-III-pyrrolo[ 3,2-c]quinolin-2-yl]ethyl]pyridine-2-carboxamide; bis(trifluoroacetic acid) (11.1 mg, 10.4%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=398.2. 1H NMR (300 MHz, methanol d ₄ , ppm) δ 8.62 (s, 1H), 8.09 (t, J=6.7 Hz, 2H), 7.97-7.89 (m, 3H), 7.77 (d, J=2.2 Hz, 1H), 7.56 (s, 1H), 6.81 (s, 2H), 3.86 (t, J=7.0 Hz, 2H), 3.31 (s, 4H), 3.18 (t, J=6.9 Hz, 2H).

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Example 156 Preparation of 2-[(oxolan-2-yl)methyl]-7-(III-pyrazol-5-yl)-III-pyrrolo[3,2-c]quinoline-4-amine

Stage 1. Synthesis of 7-bromo-3-iodoquinoline-4-ol.

Solution of 7-bromoquinolin-4-ol (11 g, 49.095 mmol, 1 eq.) and iodine(sulfanyl)amine (10.25 g, 58.9 mmol, 1.2 eq.) in CH ₃ CN (200 ml) stirred for 2 h at 65°C. The precipitated solids were collected by filtration and washed with acetonitrile (3x10 ml). This resulted in 7-bromo-3-iodoquinolin-4-ol (15.7 g, 91.4%) as a yellow solid. LC-MS: (ES, m/z): [M+H]+=349.9.

Stage 2. Synthesis of 7-bromo-4-chloro-3-iodoquinoline.

Solution of 7-bromo-3-iodoquinolin-4-ol (15.7 g, 44.8 mmol, 1 eq.) and phosphoryl trichloride (20.64 g, 134.59 mmol, 3 eq.) in dioxane (400 ml , 4721.6 mmol, 105 eq.) was stirred for 2 h at 100°C. The reaction was quenched with water/ice. The mixture was neutralized to pH 8 with saturated aqueous NaHCO ₃ . The precipitated solids were collected by filtration and washed with water (3x10 ml). This resulted in 7-bromo-4-chloro-3-iodoquinoline (16 g, 96.8%) as a yellow solid. LC-MS (ES, m/z): [M+H]+=367.8.

Stage 3. Synthesis of 7-bromo-3-iodo-N-[(4-methoxyphenyl)methyl]quinoline-4-amine.

Solution of 7-bromo-4-chloro-3-iodoquinoline (16 g, 43.43 mmol, 1 eq.) and 1-(4-methoxyphenyl)methanamine (11.9 g, 86.8 mmol, 2 eq.), Hunig base (18.67 g, 130.3 mmol, 3 eq.) in DMF (400 ml) was stirred overnight at 80°C. The resulting mixture was extracted with EtOAc (3x300 ml). The combined organic layers were washed with water (3x300 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 ml). The precipitated solids were collected by filtration and washed with EtOAc (3x10 ml). The resulting mixture was concentrated under reduced pressure. This resulted in 7-bromo-3-iodo-N-[(4methoxyphenyl)methyl]quinoline-4-amine (7 g, 34.36%) as a yellow solid. LC-MS (ES, m/z): [M+H]+=468.9. ¹ H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.21 (d, J=9.1 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.60 (dd, J=9.1 , 2.1 Hz, 1H), 7.24 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.45 (t, J=6.6 Hz, 1H), 4.83 (d, J=6.6 Hz, 2H), 3.70 (s, 3H).

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Step 4. Synthesis of 7-bromo-M-[(4-methoxyphenyl)methyl]-3-[3-(oxolan-2-yl)prop-1-yn-1-yl]quinolin-4amine.

Solution of 7-bromo-3-iodo-M-[(4-methoxyphenyl)methyl]quinoline-4-amine (1 g, 2.1 mmol, 1 eq.), 2-(prop2-yn-1-yl)oxolane (704 mg, 6.4 mmol, 3 eq.), CuI (40 mg, 0.21 mmol, 0.1 eq.), Pd(PPh ₃ ) ₂ Cl ₂ (748 mg, 1.06 mmol, 0, 5 eq.) and triethylamine (1.08 g, 10.66 mmol, 5 eq.) in ethoxyethane (20 ml) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give 7-bromo-N-[(4-methoxyphenyl)methyl]-3-[3-(oxolan-2-yl)prop-1- in-1yl]quinoline-4-amine (560 mg, 58.2%) as a yellow solid. LC-MS (ES, m/z): [M+H]+=451.1.

Step 5. Synthesis of 7-bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2c]quinoline.

7-Bromo-N-[(4-methoxyphenyl)methyl]-3-[3-(oxolan-2-yl)prop-1-yn-1-yl]quinoline-4-amine solution (560 mg, 1.24 mmol, 1 eq.) and t-BuOK (278.44 mg, 2.48 mmol, 2 eq.) in 1-methylpyrrolidin-2-one (5 ml) were stirred overnight at 65° C. under nitrogen. The reaction was quenched with a saturated solution of NH ₄ Cl (aq.) at 0°C. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water, gradient from 10% to 50% in 10 min; detector, UV 254 nm. This resulted in 7-bromo-1-[(4-methoxyphenyl)methyl]-2[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2-c]quinoline (320 mg, 57.1% ) as a yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =451.1 ¹ H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.21 (d, J=2.1 Hz, 1H) , 8.09 (d, J=9.1 Hz, 1H), 7.55 (dd, J=9.0, 2.1 Hz, 1H), 6.85 (s, 4H), 6.82 (s, 1H), 5.85 (s, 2H), 4.16 ( q, J=6.4 Hz, 1H), 3.77 (q, J=6.9 Hz, 1H), 3.62 (q, J=7.4 Hz, 1H), 2.99 (dd, J=5.8, 4.0 Hz, 2H), 2.01 ( ddd, J=12.1, 6.8, 4.4 Hz, 1H), 1.85-1.77 (m, 2H), 1.62-1.55 (m, 1H).

Step 6. Synthesis of 7-bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2c]quinoline-5-ium-5-olate.

7-Bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2-c]quinoline solution (320 mg, 0.71 mmol, 1 eq.) and mCPBA (349 mg, 1.42 mmol, 2 eq., 70%) in dichloromethane (10 ml) were stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 30:1) to give 7-bromo-1-[(4methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3.2 -c]quinoline-5-ium-5-olate (200 mg, 60.4%) as a yellow solid. LC-MS: (ES, m/z): [M+H] ⁺ =467.1.

Step 7. Synthesis of 7-bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2c]quinoline-4-amine.

7-Bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2-c]quinoline-5ium-5-olate solution (200 mg, 0.428 mmol, 1 eq) and NH4OH (3.00 ml, 85.601 mmol, 180.03 eq) in dichloromethane (9 ml) were stirred for 5 min at room temperature. TsCl (163.17 mg, 0.856 mmol, 2 eq) was then added to the above mixture and stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) to give 7-bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1Hpyrrolo[3.2 -c]quinoline-4-amine (160 mg, 80.17%) as a yellow solid. LC-MS (ES, m/z): [M+H] ⁺ =466.1.

Step 8. Synthesis of 1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-7-(1H-pyrazol-5-yl)-1Hpyrrolo[3,2-c]quinolin- 4-amines.

7-Bromo-1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-1H-pyrrolo[3,2-c]quinoline-4amine solution (160 mg, 0.34 mmol , 1 eq.) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (133 mg, 0.68 mmol, 2 eq.), Cs ₂ CO ₃ (335 mg, 1.0 mmol, 3 eq.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (56 mg, 0.069 mmol, 0.2 eq.) in 1,4-dioxane (5 ml) , water (0.5 ml) was stirred for 3 h at 90° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 8:1) to give 1-[(4-methoxyphenyl)methyl]-2-[(oxolan-2-yl)-methyl]-7-(1H-pyrazol-5yl )-1H-pyrrolo[3,2-c]quinoline-4-amine (100 mg, 64.27%) as a yellow solid. LC-MS (ES, m/z): [M+H]+=454.2.

Step 9 Synthesis of 2-[(oxolan-2-yl)methyl]-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine.

1-[(4-Methoxyphenyl)methyl]-2-[(oxolan-2-yl)methyl]-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2c]quinoline-4 solution α-amine (40 mg, 0.088 mmol, 1 eq.) and trifluoromethanesulfinic acid (0.5 ml) in 2,2,2-trifluoroacetaldehyde (2 ml) were stirred for 3 hours at room temperature under nitrogen. The residue was basified to pH 8 with saturated aqueous Na ₂ CO ₃ . The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by preparative HPLC using the following conditions (column: Xbridge Prep C18 OBD, 19x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH3.H2O) , mobile phase B: ACN; flow rate: 25 ml/min; gradient: 15 to 35% B over 7 min; 254/210 nm; RT: 6.37 min) to give 2-[(oxolan-2yl)methyl ]-7-(1H-pyrazol-5-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine (3.7 mg, 12.58%) as a light yellow solid. LC-MS: (ES, m/z): [M+H]+=334.2. 1Н NMR (400 MHz, methanol-d ₄ ) δ 8.10 (s,

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1H), 7.98 (s, 1H), 7.81-7.79 (m, 1H), 7.71 (s, 1H), 6.78 (s, 1H), 6.69 (s, 1H), 4.29-4.22 (m, 1H), 3.95 -3.90 (m,

1H), 3.81-3.76 (m, 1H), 3.31-3.30 (m, 2H), 2.18-2.05 (m, 1H), 1.97-1.90 (m, 3H), 1.74-1.66 (m, 1H), 1.28- 1.23(m, 1H).

Example 157 Preparation of N-{2-[4-amino-7-(III-pyrazol-5-yl)-2H-[1.2.3]triazolo[4.5-c]quinolin-2yl]ethyl}- 2-fluoro-2-methylpropanamide.

stage 1 ~ stage 2

CI

stage 7

Step 1. Synthesis of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-3-ium-3olate.

In a 500 ml round bottom flask were added 7-bromo-4-chloro-3-nitroquinoline (10.64 g, 37 mmol, 1 eq.) and TEA (22.47 g, 222 mmol, 6 eq.) in DCM (200 ml), then [(4methoxyphenyl)methyl]hydrazine dihydrochloride (12.5 g, 55.5 mmol, 1.5 eq.) was added. The resulting solution was stirred for 1 day at room temperature. The resulting solution was extracted with dichloromethane 3x200 ml, the organic layers were combined and concentrated. This resulted in 11 g (77%) of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-3-ium-3- olata as a red solid. LC-MS: (ES, m/z): [M+H]+=385.2.

Stage 2. Synthesis of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline.

7-Bromo-2-[(4-methoxyphenyl)methyl]-2H[1,2,3]triazolo[4,5-c]quinoline-3-ium-3-olate (11 g , 28.5 mmol, 1 eq.) in toluene (100 ml) and CHCl ₃ (100 ml), then HMPA (20 ml) and PCl ₃ (31.07 g, 228 mmol, 8 eq.) were added sequentially. The resulting solution was stirred for 1 day at 100°C. The resulting mixture was concentrated. The pH of the solution was adjusted to 7-8 with NaHCO ₃ . The residue was applied to a silica gel column and eluted with dichloromethane/ethyl acetate (30:1). This resulted in 5.7 g (54%) of 7-bromo-2-[(4-methoxyphenyl)methyl]2H-[1,2,3]triazolo[4,5-c]quinoline as a brown solid. LC-MS: (ES, m/z): [M+H]+=369.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.35 (s, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.07 (dd, J= 8.5, 1.9 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 5.94 (s, 2H), 5.76 (s, 1H), 3.74 (s, 3H).

Stage 3. Synthesis of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-5-ium-5-olate.

7-bromo-2-[(4-methoxyphenyl)methyl]-2H

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[1,2,3]triazolo[4,5-c]quinoline (6.8 g, 18.4 mmol, 1 eq.) in MeOH (70 ml) and H ₂ O ₂ (70 ml), then MTO was added (2.30 g, 9.2 mmol, 0.50 eq.). The resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column eluting with dichloromethane/ethyl acetate (15:1). This resulted in 5.7 g (80%) of 7-bromo-2-[(4methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-5-ium-5- olata as a yellow solid. LC-MS: (ES, m/z): [M+H]+=385.2.

Stage 4. Synthesis of 7-bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline.

7-Bromo-2-[(4-methoxyphenyl methyl]-2H[1,2,3]triazolo[4,5-c]quinoline-5-ium-5-olate (4.2 g, 10.9 mmol, 1 eq.) and DMF (2 ml) in DCM (100 ml), then POCl ₃ (2.51 g, 16.354 mmol, 1.5 eq.) was added. The resulting solution was stirred for 1 night at 40° C. The resulting solution was extracted with dichloromethane 3x100 ml, the organic layers were combined and concentrated to give 4.5 g of 7-bromo-4-chloro-2-[(4-methoxyphenyl)methyl]-2H[1, 2,3]triazolo[4,5-c]quinoline as brown crude solid LC-MS: (ES, m/z): [M+H]+=403.0.

Step 5. Synthesis of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine.

7-bromo-4-chloro-2-[(4methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline (4.5 g, 11.148 mmol, 1 equiv.) in dioxane (50 ml) and NH3H2O (50 ml). The resulting solution was stirred for 1 night at 110°C. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using dichloromethane/ethyl acetate (10:1). The resulting mixture was concentrated. This resulted in 2.7 g (63%) of 7-bromo-2-[(4-methoxyphenyl)methyl]-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine as a brown solid. LC-MS: (ES, m/z): [M+H]+=384.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (d, J=8.4 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.49 (s, 2H), 7.40 (dd, J= 8.4, 1.7 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 6.95 (d, J=8.6 Hz, 2H), 5.93 (s, 2H), 3.74 (s, 3H).

Stage 6. Synthesis of 7-bromo-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine.

7-bromo-2-[(4-methoxyphenyl)-methyl]-2H[1,2,3]triazolo[4,5-c]quinoline-4-amine (1.12 g, 2.9 mmol, 1 eq.) and TFA (30 ml). The resulting solution was stirred for 16 h at 80°C. The resulting mixture was concentrated. This resulted in 1,3 7-bromo-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine as a brown crude solid. LC-MS: (ES, m/z): [M+H]+=264.0.

Step 7. Synthesis of 7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine.

To a 100 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was added 7-bromo-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine (1.3 g, 4.923 mmol , 1 eq.), Cs ₂ CO ₃ (4.81 g, 14.768 mmol, 3 eq.), 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (2.74 g, 9.845 mmol, 2.00 eq.), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (804.00 mg, 0.985 mmol, 0 .2 eq.) in dioxane (20 ml) and H ₂ O (4 ml). The resulting solution was stirred for 16 hours at 90°C. The resulting mixture was concentrated. The residue was applied to a silica gel column using dichloromethane/methanol (8:1). This resulted in 1.2 g (72%) of 7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H-[1,2,3]triazolo[4,5-c ]quinoline4-amine as a dark green solid. LC-MS: (ES, m/z): [M+H] ⁺ =336.1.

Step 8. Synthesis of tert-butyl N-(2-[4-amino-7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H[1,2,3]triazolo)[ 4,5-c]quinolin-2-yl]ethyl)carbamate.

7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H[1,2,3]triazolo[4,5-c]quinoline-4-amine was added to a 500 ml round bottom flask. (1.5 g, 4.47 mmol, 1 eq.) in DMF (30 ml) followed by tert-butyl N-(2-bromoethyl)carbamate (2.00 g, 8.9 mmol, 2 eq.) and Cs ₂ CO ₃ (4.37 g, 13.4 mmol, 3 eq.). The resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated. Solids were collected by filtration. This resulted in 1.5 g (70%) tert-butyl N-(2-[4-amino-7-[1(oxan-2-yl)-1H-pyrazol-5-yl]-2H-[1 ,2,3]triazolo[4,5-c]quinolin-2-yl]ethyl)carbamate as a brown solid. LC-MS: (ES, m/z): [M+H]+=479.2. 1H NMR (300 MHz, DMSO-d ₆ ) δ 8.18 (d, J=8.1 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.36 (s, 2H), 7.07 (t, J=5.8 Hz, 1H), 6.55 (s, 1H), 5.375.26 (m, 1H), 4.79 (t, J=5.4 Hz, 2H), 4.12-3.98 (m, 1H), 3.58 (t, J=7.7 Hz, 3H), 2.49-2.31 (m, 2H), 2.04-1.89 (m, 1H), 1.87-1.74 (m, 1H), 1.69-1.49 (m , 3H), 1.31 (s, 9H).

Step 9. Synthesis of 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-2H-[1,2,3]triazolo[4,5-c]quinoline-4-amine.

tert-Butyl N-(2-[4-amino-7-[1-(oxan-2-yl)-1Hpyrazol-5-yl]-2H-[1,2,3]triazolo [4,5-c]quinolin-2-yl]ethyl)carbamate (1.2 g, 2.508 mmol, 1 eq.) in HCl in 1,4-dioxane (4 N, 20 mL). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated. The resulting solution was extracted with dichloromethane 3x100 ml and the aqueous layers were combined. This resulted in 1.1 g of 2-(2-aminoethyl)-7-(III-pyrazol-5-yl)-2H[1,2,3]triazolo[4,5-c]quinoline-4-amine in as a brown crude solid. LC-MS: (ES, m/z): [M+H] ⁺ =295.1.

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Step 10. Synthesis of N-[2-[4-amino-7-(1H-pyrazol-5-yl)-2H-[1,2,3]triazolo[4,5-c]quinolin-2-yl]ethyl ]2-fluoro-2-methylpropanamide.

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-2H[1,2,3]triazolo[4,5-c]quinoline-4-amine (40 mg, 0.13 mmol, 1 eq.) and 2-fluoro-2-methylpropanoic acid (14.4 mg, 0.13 mmol, 1 eq.) in DCM (4 mL) followed by HATU (103.3 mg, 0.27 mmol, 2 eq.) and DIEA (52.6 mg, 0.4 mmol, 3 eq.). The resulting solution was stirred for 16 hours at room temperature. The resulting mixture was concentrated. The crude product was dissolved in MeOH (4 ml), NaOH (10.8 mg, 0.27 mmol, 2 eq.) was added. The resulting solution was stirred for 2 hours at 70°C. The resulting mixture was concentrated. The residue was applied to a silica gel column eluting with dichloromethane/methanol (10:1) to give the crude product. The crude product was further purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18, 30x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 8 to 45% B in 7 min; 254/210 nm; RT: 6.45 min. This resulted in 4 mg (7.70%) N-[2[4-amino-7-(1 H-pyrazol-5-yl)-2H-[ 1,2,3]-triazolo[4,5- c]quinolin)-2-yl]ethyl]-2-fluoro-2-methylpropanamide as a white solid. LC-MS: (ES, m/z): [M+H]+=383.4. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.22 (d, J=8.2 Hz, 1H), 8.02 (s, 1H), 7.75 (s, 2H), 6.79 (s, 1H), 5.00-4.94 ( m, 2H), 3.91 (t, J=5.7 Hz, 2H), 1.45 (d, J=21.8 Hz, 6H).

The compounds of Examples 158-162 were prepared according to synthetic procedures similar to those described in Example 157 from the appropriate starting materials. Analytical LC/MS conditions.

A: column: Ascentis Express C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: acetonitrile with 0.05% trifluoroacetic acid; mobile phase B: water with 0.05% trifluoroacetic acid; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1.5 ml/min; detection: MS and UV.

B: column: PoroShell HPH C18, 3.0x50 mm, 2.7 µm particles; mobile phase A: acetonitrile with 5 mM ammonium bicarbonate; mobile phase B: water with 5 mM ammonium bicarbonate; temperature: 40°C; gradient: 5 to 50% B in 3 min, then to 95% B in 0.2 min, then hold 1.0 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

C: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: acetonitrile with 5 mM ammonium bicarbonate; mobile phase B: water with 5 mM ammonium bicarbonate; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

Etc. No. Structure LC/MS [M+H]+ RT (min)/ LC Ή NMR unless otherwise noted, 400 MHz, Mstanol-gb 158 CI H H H ₂ NN . _N Ν UM Ν-Vn O hnA w 440.1 0.97/A 5 8.20 (d, 7= 8.2 Hz, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.79 (d, 7=32.9Hz, 2H), 6.79 (s, 1H), 5.05 -4.98 (w, 2H), 4.08 (t, 7=5.8 Hz, 2H)

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159 G IZ X X Ί X 400.2 2.29/B ¹ HNMR(300 MHz, Methanol^) δ 8.60 (d, J = 4.7 Hz, 1H), 8.17 (d, 7= 8.1 Hz, 1H), 8.06-7.96 (m, 2H), 7.94-7.86 (m, 1H ), 7.84 - 7.67 (m, 2H), 7.58- 7.48 (m, 1H), 6.79 (d, 7= 2.3 Hz, 1H), 5.05 (t, 7= 5.8 Hz, 2H), 4.16 (t, 7= 5.9Hz, 2H) 160 ⁿ H ₂ N . _N /-N γΛΑ n ⁰ yX hnA 418.4 1.42/B 5 8.49 (d, 7= 2.9 Hz, 1H), 8.18 (d, 7= 8.2 Hz, 1H), 8.10 (dd, 7= 8.7, 4.6 Hz, 1H), 8.00 (s, 1H), 7.72 (td, 7=8.6, 2.8Hz, 3H), 6.79 (d, 7= 2.2Hz, 1H), 5.04 (t, 7= 5.8Hz, 2H), 4.14 (t, 7= 5.8Hz, 2H) 161 nh ₂ I 1 CH ₃ Ζγ ^N \_ _N ' n-XLJ ^bn z M 323.2 1.53/B 5 8.24 (d, 7= 8.3 Hz, 1H), 8.06 (s, 1H), 7.93-7.57 (m, 2H), 6.80 (s, 1H), 5.024.95 (m, 2H), 3.17(t.7 = 6.4Hz, 2H), 2.37(s, 6H) 162 nh ₂ ^och ₃ 1 1 ^N — 310.1 1.24/C ΉΉΜΡ(300 MHz, Methanol^) 5 8.24 (d, 7 = 8.2 Hz, 1H), 8.01 (s, 1H), 7.75 (d, 7= 18.1 Hz, 2H), 6.79 (d, 7= 2.2 Hz, 1H ), 5.00-4.97 (m, 2H), 4.11 (t, 7= 5.2 Hz, 2H), 3.38 (s, 3H)

The compounds of examples 163-184 were prepared according to synthetic procedures similar to those described in example 20, example 31 or example 132 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-de)

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163 Al ¹ “Ί I 356.1 0.93 5 8.63 (s, 1H), 8.52 (brd, 7=4.1 Hz, 1H), 7.87 (br d, 7=5.5 Hz, 2H), 7.75 - 7.57 (m, 3H), 7.25 -7.21 (m, 2H) , 6.79 (brs, 2H), 6.72 (s, 1H), 4.84 (brt, 7=7.0 Hz, 2H); signals of two CH protons are not observed, apparently due to overlap with the peak corresponding to water 164 H 1 H ₂ N \—// NY Г 11 ⁰ N=< ΗΝχΖ 402.2 1.18 5 10.32 (brs, 1H), 8.74 (s, 1H), 7.97 (brd,7=8.0 Hz, 1H), 7.90 (brs, 2H), 7.81 7.56 (br, 2H), 7.33 - 7.26 (br, 1H) , 7.23 -7.13 (brs, 2H), 6.78 (brs, 2H), 6.74 (s, 1H), 5.49 (s, 2H) 165 nh ₂ 1 ';. HN T ^N 342.2 0.57 5 13.79-13.51 (br, 1Н), 13.24-12.90 (br, 1Н), 9.849.26 (br, 2Н), 9.13 (s, 1Н), 8.59 (d,7=5.8 Hz, 2Н), 8.14 (brd ,7=8.0 Hz, 2H), 7.91 (br d, 7=8.5 Hz, 1H), 7.87 - 7.80 (br, 1H), 7.27 (d, 7=5.8 Hz, 2H), 6.79 (d, 7=1.7 Hz, 1H), 5.87 (s, 2H) 166 CH ₃ ^H2 \ N K ch ₃ O m \u003d / HN ^ 372.9 1.13 5 8.40 (s, 1H), 7.87 (s, 1H), 7.84 (d, 7=8.0 Hz, 1H), 7.69 (br s, 1H), 7.60 (br d, 7=7.2 Hz, 1H), 6.83 - 6.74 (br, 2H), 6.72 (d, 7=1.9 Hz, 1H), 5.68 (s, 1H), 4.78 (brt, 7=5.8 Hz, 2H), 4.48 (brt, 7=5.8 Hz, 2H), 2.09 (s, ZN), 1.83 (s, ZN) 167 νη ₂ ,:+ < 342.1 0.75 5 8.85 (s, 1H), 8.64 (s, 1H), 8.54 (d,7=3.9 Hz, 1H), 7.967.91 (br, 1H), 7.89 (s, 1H), 7.73 (brd, 7=8.0 Hz, 1H), 7.69 (br s, 1H), 7.62 (br d, 7=8.0 Hz, 1H), 7.41 (dd, 7=7.6, 4.5 Hz, 1H), 6.82 6.75 (br, 2H), 6.74 ( d, 7=1.9 Hz, 1H), 5.74 (s, 2H) 168 τ ζ £> br z' VsZ 348.1 0.87 5 13.12-12.66 (br, 1H), 9.10 (d, 7=1.7 Hz, 1H), 8.79 (s, 1H), 7.96 (br d, 7=8.0 Hz, 1H), 7.89 (brs, 1H), 7.827 .56 (w, 3h), 6.87 - 6.77 (w, 2h), 6.74 (s, 1h), 5.81 (s, 2h)

- 101 042018

169 H ₂ NN^ _n xx.N Y'A N\ ^P θ-N Np ηνΡ 409.1 1.36 δ 13.42-12.74 (m, 1H), 8.97 (s, 1H), 8.02 - 7.96 (m, 3H), 7.91 (s, 1H), 7.77 - 7.52 (m, 5H), 6.85 (br s, 2H), 6.75(d, 7=1.7Hz, 1H), 6.26(s, 2H) 170 ΞΕ Αί Ρρρ Κ ^ζ ι ο ^S O ΞΕ CO 357.3 0.93 δ 8.81 (s, 1H), 7.94 (brd, 7=8.3 Hz, 2H), 7.85 - 7.52 (m, 2H), 7.22 - 6.84 (m, 2H), 6.74 (br s, 1H), 4.90 (t, 7=7.0Hz, 2H), 3.90(t, 7=6.6Hz, 2H), 2.98(s, 3H) 171 CO I Ο ^θ Pl pOO^ ¹ ip* ^Z PI 371.2 0.98 δ 13.70-12.89 (m, 1H), 9.84-9.11 (m, 2H), 9.00 (s, 1H), 8.14-8.08 (m, 2H), 7.90 (d, 7=7.9 Hz, 1H), 7.82 (br s, 1H), 6.79 (d, 7=2.1 Hz, 1H), 4.67 (t, 7=7.0 Hz, 2H), 3.263.22 (m, 2H), 3.00 (s, 3H), 2.46 - 2.38 (m , 2H) 172 ^P + pP/L iPjP N~pP yp N=P hnP 409.1 1.22 δ 13.04-12.70 (m, 1H), 8.97 (s, 1H), 8.00 (brd,7=7.9Hz, 1H), 7.98 (s, 1H), 7.97 (d, 7=1.5Hz, 1H), 7.91 ( brs, 1H), 7.83 - 7.56 (m, 5H), 7.05 -6.91 (m, 2H), 6.75 (s, 1H), 6.17 (s, 2H) 173 CO ΞΕ O A VP P=PX ¹ L ^z 'z' I 346.1 1.11 δ 13.44-12.75 (m, 1H), 8.84 (s, 1H), 7.95 (brd,7=8.1Hz, 1H), 7.90 (s, 1H), 7.80 - 7.57 (m, 2H), 6.98 - 6.79 (m , 2H), 6.74 (d, 7=1.7 Hz, 1H), 6.21 (s, 1H), 5.74 (s, 2H), 2.37 (s, 3H) 174 ^H P p PC N^^N N P/ Ii \\ _CH Uf N. ₀ + ^CH p N=Z pp 347.3 0.84 δ 13.43 - 12.77 (m, 1H), 8.85 (s, 1H), 7.97 (br d, 7=7.4 Hz, 1H), 7.89 (brs, 1H), 7.81 7.56 (m, 2H), 6.84-6.71 (m , 3H), 5.86 (s, 2H), 2.58 - 2.55 (m, 3H)

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175 z^ yi ¹ ΙΓΑ I 345.1 0.89 5 8.67 (s, 1H), 7.91 (brd, 7=7.7 Hz, 2H), 7.74 - 7.68 (m, 1H), 7.65 (brd, 7=7.4 Hz, 1H), 7.61 (s, 1H), 7.30 - 6.96 (m, 2H), 6.79 (s, 1H), 6.74 (d, 7=1.9Hz, 1H), 4.69 (brt, 7=7.3Hz, 2H), 3.21 (brt, 7=7.2Hz, 2H) 176 r-0 ⁿ II ^C1 X/ ⁰ yy Ν=< ΗΝ^ 423.2 1.12 5 8.91 (s, 1H), 8.71 (brt, 7=5.6 Hz, 1H), 8.67 (s, 1H), 8.11-8.05 (m, 2H), 7.88 7.76 (m, 2H), 6.78 (brs, 1H) , 4.66 (brt,7=5.5Hz, 2H), 3.86 -3.77 (m, 2H) 177 _o ^H 2^ ^NH ⁰ N ^Z £3 HN \ 392.2 0.79 5 8.62 (s, 1H), 7.97 (brt, 7=5.7 Hz, 1H), 7.94 - 7.87 (m, 2H), 7.69 (br s, 1H), 7.62 (br d, 7=7.9 Hz, 1H), 6.84-6.71 (m, 3H), 4.52 (brt, 7=5.8 Hz, 2H), 4.17-4.12 (m, 1H), 3.81-3.75 (m, 2H), 3.72-3.64 (m, 2H), 2.07- 1.97 (m, 1H), 1.79-1.61 (m, 3H) 178 ^Η Λ N ₄ H 0^ N^\^N ₄ / n ;— ⁷ // ° O N=/ HN^ 434.1 0.95 5 8.67 (s, 1H), 8.09 (t, 7=5.8 Hz, 1H), 7.92 (d, 7=8.1 Hz, 1H), 7.89 (d, 7=1.4 Hz, 1H), 7.69 (br s, 1H ), 7.62 (br d, 7=8.5 Hz, 1H), 6.73 (d, 7=2.1 Hz, 1H), 6.88 - 6.71 (m, 2H), 4.53 (t, 7=6.0 Hz, 2H), 4.124. 03 (m, 4H), 3.69-3.64 (m, 2H) 179 ^H ANH O-'y 'N'\._N 1 1 N \-M ' Y\,M %% o ^snz / / N=i enantiomer 1 HN ₄ D> 421.4 0.62 5 8.63 (s, 1H), 7.99 - 7.89 (m, 3H), 7.76 - 7.59 (m, 2H), 6.97 -6.80 (m, 2H), 6.74 (d, 7=1.9 Hz, 1H), 4.57 - 4.45 (m, 2H), 3.86 (dd, 7=10.0, 2.6 Hz, 1H), 3.82 (brd,7=11.3 Hz, 1H), 3.70 -3.58 (m, 2H), 3.563.49 (m, 1H), 2.78 (brd, 7=11.0 Hz, 1H), 2.57-2.54 (m, 1H), 2.13 (s, 3H), 1.96 (td, 7=11.3, 2.9 Hz, 1H), 1.80 (t, 7=10.7 Hz , 1H) 180 Η,Ν ,, .-h ^g ™ N H °' \ T-A 'N-'XN JI W 'y'\,-N O ^CH3 Ν \u003d γ enantiomer 2 ΗΝ„ D 421.1 0.62 δ 8.64 (s, 1H), 7.99 - 7.89 (m, 3H), 7.76 - 7.59 (m, 2H), 7.01 - 6.83 (m, 2H), 6.74 (d, 7=1.7 Hz, 1H), 4.57-4.46 (m, 2H), 3.86 (dd, 7=10.0, 2.6 Hz, 1H), 3.82 (brd, 7=11.3 Hz, 1H), 3.70 - 3.58 (m, 2H), 3.53

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(td, 7=11.1, 2.3 Hz, 1H), 2.78 (brd, 7=11.8 Hz, 1H), 2.57-2.54 (m, 1H), 2.13 (s, 3H), 1.96 (td, 7=11.2, 2.9 Hz, 1H), 1.80 (t, 7=10.7 Hz, 1H) 181 I /-g Luu ² ZI °? w 404.1 1.02 δ 8.65 (s, 1H), 8.46 - 8.39 (m, 1H), 7.93 - 7.86 (m, 2H), 7.69 (br s, 1H), 7.62 (br d, 7=7.7 Hz, 1H), 6.85 6.70 ( m, 3H), 4.53 - 4.47 (m, 2H), 3.71 -3.64 (m, 2H), 3.30-3.22 (m, 2H) 182 Z /K /° /^o IZ z^ X 387.2 1.01 δ 8.65 (s, 1H), 8.38 (t, 7=5.5 Hz, 1H), 7.93 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.74 - 7.65 (m, 1H), 7.63 ( brd, 7=8.0 Hz, 1H), 6.75 - 6.65 (m, 3H), 4.53 (t, 7=5.6 Hz, 2H), 3.67-3.61 (m, 2H), 1.55 - 1.50 (m, 2H), 1.44 - 1.39 (m, 2H). 183 $ ⁰ nn (/ Λ 403.1 1.13 5 8.67 (s, 1H), 8.47 (d, 7=2.1 Hz, 1H), 8.37 (s, 1H), 8.33 (br t, 7=5.1 Hz, 1H), 7.98 (d, 7=8.5 Hz, 1H ), 7.87 (d, 7=1.8 Hz, 1H), 7.73 (s, 1H), 7.66 (dd, 7=8.4, 1.9 Hz, 1H), 6.68 (br s, 2H), 6.53 (s, 1H), 4.62 (t, 7=6.3Hz, 2H), 3.83 (q, 7=6.1Hz, 2H), 2.43 (s, 3H) 184 I A 1 X^Zχ,χ^χ.Z Z LI! A? z zx /=2 417.1 1.24 5 8.89 (brt, 7=5.6 Hz, 1H), 8.69 (s, 1H), 8.59 (d, 7=2.6 Hz, 1H), 8.47 (d, 7=2.2 Hz, 1H), 8.09 (dd, 7= 8.8, 4.7 Hz, 1H), 7.97 (d, 7=8.5 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.73 (s, 1H), 7.65 (dd, 7=8.3, 1.8 Hz, 1H), 6.68 (br s, 2H), 6.53 (s, 1H), 4.67 (t, 7=6.2 Hz, 2H), 3.91 (q, 7=6.3 Hz, 2H)

The compounds of examples 185-193 were prepared according to synthetic procedures similar to those described in example 20, example 31 or example 132 from the appropriate starting materials. Analytical LC/MS conditions.

A: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

B: column: Shim-pack XR-ODS, 3.0x50 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 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

C: column: Kinetex EVO C18, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

- 104042018

Etc. No. Structure LC/MS [M+H] ⁺ RT (min)/ LC conv. Ή NMR, unless otherwise noted, 300 MHz, MstanolX 185 nh ₂ ^OCH3 Η ν22 309.2 0.98/A δ 8.59 (s, 1H), 7.98 (t, 7= 10.2 Hz, 2H), 7.71 (s, 2H), 6.75 (s, 1H), 4.67 (t, 7= 5.1 Hz, 2H), 3.94 (t, 7= 5.1 Hz, 2H), 3.38 (s, 3H) 186 7 ^H 2 CH ₃ n G]^ ⁷ n^222 M 307.2 1.13/B Ή NMR (400 MHz, MstanolX) δ 8.77 (s, 1H), 8.09 (d, 7=8.3 Hz, 1H), 8.02 (d,7= 1.6 Hz, 1H), 8.02-7.97 (m, 1H), 7.77 (d, 7=2.3 Hz, 1H), 6.82 (d, 7=2.4 Hz, 1H), 4.57 (t, 7= 7.1 Hz, 2H), 2.121.94 (m, 2H), 1.47-1.35 (m, 2H), 1.02 (t, 7= 7.4Hz, 3H) 187 z _χ 2g w ) ( o z' S 293.1 1.17/A Ή NMR (300 MHz, DMSO7 ₆ ) δ 13.09 (d,7= 135.0 Hz, 1H), 8.73 (s, 1H), 8.11-7.89 (m, 2H), 7.88-7.49 (m, 2H), 6.93 -6.62 (m, 3H), 4.41 (t,7 = 7.0Hz, 2H), 2.18-1.78 (m, 2H), 0.91 (t, 7= 7.4Hz, 3H) 188 nh ₂ νΛ^Ν SNz I 1 Ν—' H Μ 279.1 1.08/C δ 8.58 (s, 1H), 7.96 (t, 7= 8.4 Hz, 2H), 7.70 (s, 2H), 6.74 (d, 7= 2.2 Hz, 1H), 4.54 (q, 7 = 7.3 Hz, 2H) , 1.66 (t, 7= 7.3 Hz, 3H) 189 nh ₂ O n^n 7 Γ x nh ₂ ^h Fj^ ⁷ 322.1 0.84/C δ 8.55 (s, 1H), 7.97 (d,7= 8.1 Hz, 2H), 7.71 (s, 2H), 6.74 (s, 1H), 4.79 (t, 7= 6.6 Hz, 2H), 2.98 (t, 7= 6.6Hz, 2H) 190 r~ CH ₃ kJCi 323.2 1.12/C δ 8.57 (s, 1H), 7.97 (t, 7= 9.0 Hz, 2H), 7.70 (s, 2H), 6.74 (s, 1H), 4.66 (t, 7= 5.2 Hz, 2H), 3.98 (t, 7= 5.2 Hz, 2H), 3.54 (q, 7= 7.0 Hz, 2H), 1.16 (t, 7 = 7.0 Hz, 3H) 191 nh ₂ o _n A^n Vnh ₂ 1 1 n— ^'n Ki ^-^222 V 308.1 0.76/A δ 8.61 (s, 1H), 7.98 (t, 7= 11.1 Hz, 2H), 7.70 (s, 2H), 6.74 (s, 1H), 5.25 (s, 2H) 192 nh _{2 N} ®χΝ CHF ₂ I 1 N— ^'n Ki ^-^222 315.1 1.10/C 6 8.64 (s, 1H), 8.12-7.89 (m, 2H), 7.71 (s, 2H), 6.74 (s, 1H), 6.60-6.21 (m, 1H), 5.02-4.91 (m, 2H) 193 nh ₂ n^n ch ₂ fff N—' ⁿ GG ⁷ ^=222 297.1 1.01/A Ή NMR (400 MHz, Methanol-7 ₄ ) δ 8.71-8.42 (m, 1H), 8.21-7.56 (m, 4H), 6.91-6.52 (m, 1H), 5.204.92 (m, 3H), 4.81- 4.71(m, 1H)

Examples 179 and 180.

The racemic product was prepared from the appropriate starting compounds and purified with preparative chiral SFC using the following conditions to give Example 179 and Example 180 as separate undetermined isomers: Instrument: Waters 100 Prep SFC;

column: Chiral AS, 30x250 mm. 5 µm; mobile phase: 65% CO ₂ /35% IPA with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Compound of Example 179 (first eluting isomer), retention time: 3.87 min. Compound of Example 180 (second eluting isomer), retention time: 12.58 min.

Analytical Chiral SFC Conditions: Instrument: Shimadzu Nexera UC SFC; column: Chiralpak AS,

4.6x100mm, 5 micron; mobile phase: 65% CO ₂ /35% IPA with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Compound of Example 179 (first eluting isomer), retention time: 2.5 min. Example 180 compound (second eluting isomer). Retention time: 5.6 min.

Example 194 Preparation of 7-(1H-pyrazol-3-yl)-2-(2-(pyridin-2-ylamino)ethyl)-2H-pyrazolo[3.4

c]quinoline-4-amine.

Step 1. 2-(2-(pyridin-2-ylamino)ethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[3,4 -c]quinoline-4-amine.

A mixture of 2-(2-aminoethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)-2H-pyrazolo[3,4s]quinoline-4-amine ( 40 mg, 0.106 mmol) and sodium carbonate (44.9 mg, 0.424 mmol) were evacuated and refilled with N2, then DMSO (1060 µl) was added. The resulting mixture was purged with N2 for 10 min, then 2-bromopyridine (11.12 µl, 0.117 mmol), N,N'-dimethylethylenediamine (34.2 µl, 0.318 mmol) and copper(1) iodide (30.3 mg , 0.159 mmol). The mixture was purged with N2 for 1 min, then sealed and stirred at 120°C for 18 h. Additional 2-bromopyridine (11.12 µl, 0.117 mmol) was added and the reaction mixture was stirred at 120°C for 1 h. amount of 2-bromopyridine (25 µl) and the reaction mixture was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H2O (20 ml), 1:1 H ₂ O-a . NH ₄ OH (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give 2-(2(pyridin-2-ylamino)ethyl)-7-(1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[3,4c]quinoline-4-amine (4.3 mg, 9%). LC-MS m/z 455 [M+H]+.

Step 2 7-(1H-pyrazol-3-yl)-2-(2-(pyridin-2-ylamino)ethyl)-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a solution of 2-(2-(pyridin-2-ylamino)ethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2Hpyrazolo[3,4-c ]quinoline-4-amine (4.3 mg, 9.46 μmol) in CH ₂ Cl ₂ (0.1 ml) was added TFA (0.1 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH ₂ Cl ₂ and concentrated. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS using the following conditions: column: XBridge C18, 200x19 mm, particles 5 µm; 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 min hold at 1% B, 1-23% B for 25 min, then 2 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 7-(1H-pyrazol-3-yl)-2-(2-(pyridin-2ylamino)ethyl)-2H-pyrazolo[3,4-c]quinoline -4-amines, 2 TFA (2.6 mg, 46%). 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 8.13-8.09 (m, 2H), 7.99 (br d, J=6.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.79 (s, 1H), 7.55-7.48 (m, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.67-6.60 (m, 2H), 4.73 (t, J=5.9 Hz, 2H ), 3.94 (br t, J=5.8 Hz, 2Н). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1%

- 106 042018 trifluoroacetic acid; temperature: 50°C; gradient: 0 to 100% B over 3 min, then hold 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 371.1 [M+H]+; RT: 0.92 min.

Example 195 Preparation of N-(2-(4-amino-8-chloro-7-(1H-nirazol-3-yl)-2H-nurazolo[3,4-c]quinolin-2yl)ethyl)-5-fluoropicolinamide .

Step 1. 7-bromo-8-chloro-2H-pyrazolo[3,4-c]quinoline-4-amine.

To a suspension of 7-bromo-2H-pyrazolo[3,4-c]quinoline-4-amine, TFA (0.500 g, 1.326 mmol) in CHCl ₃ (13.26 ml), -bis-(methoxycarbonyl)guanidine (0.333 g, 1.591 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with 10% MeOH-CH ₂ Cl ₂ (200 ml) and washed with saturated aqueous NaHCO ₃ (200 ml). The aqueous layer was extracted with 10% MeOH-CH ₂ Cl ₂ (3x100 ml). The combined organic layers were dried over Na ₂ SO ₄ and filtered. Celite was added and the mixture concentrated in vacuo. This product was loaded onto a column and purified by flash chromatography (RediSep Gold with 80 g silica gel with 25 g dry loaded cartridge; 0-7% MeOH-CH ₂ Cl ₂ linear gradient) to give 7-bromo-8-chloro-2Hpyrazolo[ 3,4-c]quinoline-4-amine (31 mg, 8%). LC-MS m/z 297/299 [M+H] ⁺ .

Step 2: tert-butyl (2-(4-amino-7-bromo-8-chloro-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate.

Cesium carbonate (102 mg, 0.313 mmol ) followed by tert-butyl (2 bromoethyl) carbamate (25.7 mg, 0.115 mmol). The reaction mixture was stirred at room temperature for 16 h, additional cesium carbonate (51 mg, 0.16 mmol) and tert-butyl (2-bromoethyl) carbamate (11.7 mg, 0.0522 mmol) were added. The reaction mixture was stirred at 40° C. for 2 h. The reaction mixture was diluted with EtOAc (20 ml) and H2O (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ and filtered. Celite was added and the mixture concentrated in vacuo. This product was loaded onto a dry run column and purified by flash chromatography (12 g silica gel with 5 g dry loaded cartridges; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give t-butyl (2-(4-amino -7-bromo-8-chloro-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (37 mg, 81%) as a white solid. LC-MS m/z [M+H] ⁺ ; 1Н NMR (400 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 7.10 (br s, 2H), 7.05 (br t, J=5.8 Hz , 1H), 4.45 (br t, J=6.0 Hz, 2H), 3.47 (q, J=5.9 Hz, 2H), 1.33 (s, 9H).

Step 3. tert-butyl (2-(4-amino-8-chloro-7-(1-(tetrahydro-2H-puran-2-yl)-1H-nirazol-5-yl)-2Hpyrazolo[3,4- c]quinolin-2-yl)ethyl)carbamate.

A mixture of tert-butyl (2-(4-amino-7-bromo-8-chloro-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)carbamate (20 mg, 0.045 mmol), 1-( tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazole (15.15 mg, 0.054 mmol) and tribasic phosphate potassium (28.9 mg, 0.136 mmol) was evacuated and refilled with N2, then 1,4-dioxane (189 µl) and H2O (37.8 µl) were added. The resulting mixture was purged with N2 for 15 min, then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl) was added. ]palladium(II) (1.785 mg, 2.269 µmol). The mixture was purged with N2 for

- 107 042018 min, then sealed and stirred at 100°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H ₂ O (20 ml) and saturated aqueous NaCl (20 ml) , dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOHCH ₂ Cl ₂ ) to give t-butyl (2-(4-amino-8-chloro-7-(1-(tetrahydro-2H-pyran -2-yl)-1H-pyrazol-5-yl)2H-pyrazolo[3,4-c]quinolin-2-yl)-ethyl)carbamate (17.3 mg, 75%). LC-MS m/z 512 [M+H]+.

Step 4 2-(2-aminoethyl)-8-chloro-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinoline-4-amine, 2 TFA.

To a solution of tert-butyl (2-(4-amino-8-chloro-7-(1-(tetrahydro-2H-pyran-2-yl))-1H-pyrazol-5-yl)-2Hpyrazolo[3,4- c]quinolin-2-yl)ethyl)carbamate (17.3 mg, 0.034 mmol) in CH ₂ Cl ₂ (169 μl) TFA (169 μl) was added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to remove about half the volume, then it was added dropwise to Et ₂ O (2 ml). The resulting solid was collected by vacuum filtration and washed with Et ₂ O (3x1 ml). The solids were dissolved in CH ₂ C1 ₂ -MeOH and concentrated in vacuo to give 2-(2-aminoethyl)-8-chloro-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c] quinoline-4-amine, 2 TFA (17.2 mg, 92%) as an off-white solid. LC-MS m/z 328 [M+H] ⁺ .

Step 5 N-(2-(4-amino-8-chloro-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin-2-yl)ethyl)-5fluoropicolinamide.

To a solution of 5-fluoropicolic acid (4.80 mg, 0.034 mmol) in DMF (155 µl) was added Ν,N-diisopropylethylamine (10.78 µl, 0.062 mmol) at room temperature, followed by HATU (11.77 mg, 0.031 mmol). This mixture was stirred at room temperature for 5 min, then added dropwise to a solution of 2-(2-aminoethyl)-8-chloro-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c ]quinoline-4-amine, 2 TFA (17.2 mg, 0.031 mmol) and N,N-diisopropylethylamine (16.17 μl, 0.093 mmol) in DMF (155 μl). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 11% B, 11-51% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give N-(2-(4-amino-8chloro-7-(1H-pyrazol-3-yl)-2H-pyrazolo[3,4-c]quinolin- 2-yl)ethyl)-5-fluoropicolinamide (4.2 mg, 29%). 1Н NMR (500 MHz, DMSO-d6) δ 13.33-12.92 (m, 1H), 9.06 (t, J=6.0 Hz, 1H), 8.79 (s, 1H), 8.61 (d, J=2.6 Hz, 1H) , 8.12-8.06 (m, 2H), 7.88 (td, J=8.7, 2.8 Hz, 1H), 7.85-7.66 (m, 2H), 7.36-6.96 (m, 2H), 6.72 (br s, 1H), 4.65 (br t, J=6.1 Hz, 2H), 3.88 (q, J=6.1 Hz, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 451.0 [M+H]+; RT: 1.15 min.

The compounds of examples 196-204 were prepared according to synthetic procedures similar to those described in examples 150 and 151 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

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Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMS0-d ₆ ) 196 ⁿ GU H ₂ N \ // N ^N d/ ⁰ yy N=< HN / 417.1 1.19 δ 9.06 (brt, 7=5.9 Hz, IH), 8.64 (d, 7=2.5 Hz, IH), 8.45 (s, IH), 8.12-8.06 (m, 2H), 7.92-7.86 (m, 2H), 7.71 (br s, IH), 7.63 (br d, 7=7.4 Hz, IH), 7.11 -6.84 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H), 4.63 (brt, 7=5.9 Hz , 2H), 3.85 (q, 7=6.1 Hz, 2H) 197 O c IZ SD\ ΧΎΑ £ ^r U t 433.2 1.11 δ 9.18 (brt, 7=5.8Hz, IH), 8.62 (d, 7=5.2Hz, IH), 8.53 (brs, IH), 8.08 (d,7=8.0Hz, IH), 7.99 (d, 7= 1.7 Hz, IH), 7.92 (brs, IH), 7.80-7.61 (m, 3H), 6.76 (s, IH), 4.65 (br t, 7=5.9 Hz, 2H), 3.85 (q, 7=6.0 Hz , 2H) 198 r° ^H2N v/n^Yn^ ^CH3 yy N=< hnA 403.0 0.87 δ 8.85 (s, IH), 8.50 (t, 7=5.9 Hz, IH), 8.40 (s, IH), 8.19 (d, 7=8.3 Hz, IH), 8.09 (brs, IH), 7.91 (brd, 7=8.0Hz, IH), 7.84 (brs, IH), 6.82 (d, 7=1.9Hz, IH), 4.64 (brt, 7=5.5Hz, 2H), 3.77 (q, 7=5.9Hz, 2H) , 2.43(s, 3H)

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199 ^Η!Ν ν+Ν^γθ 0 Ν=< ΗΝ^ 405.9 1.15 5 8.42 (s, 1H), 8.07 (d, 7=8.0 Hz, 1H), 7.90 - 7.86 (m, 2H), 7.71 (brs, 1H), 7.63 (brd, 7=8.0 Hz, 1H), 7.09 - 6.88 (m, 2H), 6.75 (d, 7=2.2Hz, 1H), 4.50 (brt, 7=5.4Hz, 2H), 3.92 (brd,7=11.0Hz, 1H), 3.69 (dd, 7=10.9 , 2.3 Hz, 1H), 3.64 -3.56(m, 3H), 1.84-1.78 (m, 1H), 1.74 (brd,7=10.7 Hz, 1H), 1.52 - 1.39 (m, 3H), 1.34-1.24 ( m, 1H) 200 0 N=< ΗΝ^Χ 398.2 1.16 5 8.68 (t, 7=5.5Hz, 1H), 8.46 (s, 1H), 8.08 (d, 7=8.1Hz, 1H), 7.88 (s, 1H), 7.80 - 7.76 (m, 2H), 7.76 - 7.69 (m, 1H), 7.64 (br d, 7=6.0 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.47 7.42 (m, 2H), 7.01 (br s, 2H), 6.76 (d, 7 =2.1Hz, 1H), 4.61 (brt, 7=5.8Hz, 2H), 3.78 (q, 7=5.7Hz, 2H) 201 Ιχ * XXX ^ "7 ζ- _ζ ΖΙ ъ 399.9 1.06 5 9.22 (brt, 7=5.9 Hz, 1H), 9.15 (d, 7=1.1 Hz, 1H), 8.86 (d, 7=2.4 Hz, 1H), 8.74 - 8.69 (m, 1H), 8.43 (s, 1H), 8.05 (d, 7=8.1 Hz, 1H), 7.86 (s, 1H), 7.79 - 7.58 (m, 2H), 6.95 6.83 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H) , 4.64 (brt, 7=5.8Hz, 2H), 3.86 (q, 7=5.9Hz, 2H) 202 Ν^ ⁰⁰ ^ n ii 1 Η ₂ Ν \ y Ν Π |/Λ=Ν Ο yy Ν=ξ ΗΝ^ 428.9 1.17 5 8.90 (brt, 7=5.9Hz, 1H), 8.45 (s, 1H), 8.27 (brs, 1H), 8.08 (d, 7=8.2Hz, 1H), 7.96 (d, 7=8.8Hz, 1H) , 7.87 (brs, 1H), 7.76 - 7.59 (m, 2H), 7.54 -7.48 (m, 1H), 7.05-6.88 (m, 2H), 6.76 (d, 7=2.0 Hz, 1H), 4.61 (brt , 7=5.6 Hz, 2H), 3.87 (s, 3H), 3.85-3.80 (m, 2H) 203 η ₂ ν Η CH ₃ Ν^Τ Ν^Ν I ³ \ Ζ^Ν b—\ ^υΜ 3 Ο ^{0 F} ,νΑ^ ΗΝ J 382.2 0.89 5 8.41 (s, 1H), 8.25 (brd, 7=2.5 Hz, 1H), 8.06 (d, 7=8.0 Hz, 1H), 7.87 (s, 1H), 7.70 (br s, 1H), 7.62 (br d, 7=7.7 Hz, 1H), 7.09 - 6.92 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H), 4.51 (brt, 7=5.6 Hz, 2H), 3.63 - 3.58 (m, 2H ), 1.41 (s, 3H), 1.37 (s, 3H) 204 Llau-O /\=ν ο N=< ΗΝ^ζ 399.2 1.00 5 8.93 (brs, 1H), 8.87 (t, 7=5.6 Hz, 1H), 8.68 (brd, 7=2.7 Hz, 1H), 8.46 (s, 1H), 8.11 (br d, 7=7.2 Hz, 1H ), 8.07 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.78 - 7.67 (m, 1H), 7.66-7.59 (m, 1H), 7.51 7.46 (m, 1H), 6.93 (br s, 2H), 6.75 (s, 1H), 4.61 (brt, 7=5.1 Hz, 2H), 3.79 (q, 7=5.9 Hz, 2H)

- 110 042018

Example 205 Preparation of 2-(2-(4-amino-7-(1H-pyrazol-3-yl)-2H-nirazolo[4,3-c]quinolin-2-yl)ethyl)6-fluoroisoindoline-1 - she

To a solution of 2-(2-aminoethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine, 2 TFA (40 mg, 0.077 mmol) in DMF ( 384 µl) N,N-diisopropylethylamine (66.8 µl, 0.384 mmol) and methyl 2-(bromomethyl)-5-fluorobenzoate (18.95 mg, 0.077 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. The solution was diluted with H2O (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, 200x19 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 min hold at 21% B, 21-61% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on 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)-2Hpyrazolo[4,3-c]quinolin-2-yl) ethyl)-6-fluoroisoindolin-1-one (23.1 mg, 70% yield). 1H NMR (500 MHz,

DMSO-d6) δ 13.30-12.70 (m, 1H), 8.43 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.86 (s, 1H), 7.79-7.65 (m, 1H), 7.647 .56 (m, 2H), 7.46-7.36 (m, 2H), 6.91 (br d, J=0.7 Hz, 2H), 6.75 (d, J=1.5 Hz, 1H), 4.72 (br t, J=5.4 Hz, 2H), 4.31 (s, 2H), 4.07 (br t, J=5.7 Hz, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 428 [M+H]+; RT: 1.18 min.

Example 206 Preparation of N-(2-(4-amino-7-(1H-nurazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)ethyl)methanesulfonamide.

To a solution of 2-(2-aminoethyl)-7-(1H-nurazol-3-yl)-2H-nirazolo[4,3-c]quinoline-4-amine at 0°C, 2 TFA (40 mg, 0.077 mmol ) triethylamine (42.8 µl, 0.307 mmol) and methanesulfonyl chloride (6.23 µl, 0.081 mmol) were added to DMF (256 µl). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (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, 200x19 mm, particles 5 µm; 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 min hold at 8% B, 8-48% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on 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[4,3-c]quinolin-2yl )ethyl)methanesulfonamide (18.3 mg, 64%). 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.88 (br s, 1H), 7.82-7.55 (m, 2H), 7.32- 7.25 (m, 1H), 6.76 (d, J=1.1 Hz, 1H), 4.50 (br t, J=5.4 Hz, 2H), 3.60-3.52 (m, 2H), 2.85 (d, J=2.4 Hz, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 372.2 [M+H]+; RT: 0.93 min.

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Examples 207 and 208 Preparation of 2-(2-methoxyethyl)-7-(III-pyrazol-3-yl)-2H-pyrazolo-[4,3c]quinoline-4-amine and 1-(2-methoxyethyl)-7 -(III-pyrazol-3-yl)-III-pyrazolo[4,3-c]quinoline-4-amine.

Step 1. 7-(1-(Tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine.

7-Bromo-2H-pyrazolo[4,3-c]quinolin-4-amine mixture, TFA (0.932 g, 2.47 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4.4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-III-pyrazole (1.031 g, 3.71 mmol) and tribasic potassium phosphate (1.574 g, 7.41 mmol) were evacuated and refilled with N2 , then it was mixed with 1,4-dioxane (10.30 ml) and H ₂ O (2.059 ml). The resulting suspension was purged with N2 for 15 min, then chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'biphenyl) ]palladium(II) (0.039 g, 0.049 mmol). The reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (10 ml) and H2O (10 ml). This mixture was filtered and the solid was washed with H2O (2x2 ml) and EtOAc (2x2 ml), then dried in vacuo to give 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl )-2H-pyrazolo[4,3-c]quinoline-4amine (670 mg, 81%). LC-MS m/z 335 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 8.32 (br s, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J=1.5 Hz, 1H) , 7.37 (br d, J=7.7 Hz, 1H), 7.08 (br s, 2H), 6.52 (d, J=1.5 Hz, 1H), 5.31 (dd, J=9.8, 1.9 Hz, 1H), 4.07- 3.99 (m, 1H), 3.62-3.57 (m, 1H), 2.47-2.36 (m, 1H), 2.00-1.92 (m, 1H), 1.80 (brd, J=12.9 Hz, 1H), 1.64-1.49 ( m, 3H).

Step 2. 2-(2-methoxyethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine and 1-(2methoxyethyl)-7-(1H- pyrazol-3-yl)-1H-pyrazolo[4,3-c]quinoline-4-amine.

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (29 mg, 0.087 mmol) in DMF (289 µl) cesium carbonate (85 mg, 0.260 mmol) was added followed by 2 bromoethyl methyl ether (8.97 µl, 0.095 mmol). The suspension was stirred at room temperature for 20 hours. The reaction mixture was diluted with H2O (2 ml) and extracted with EtOAc (3x2 ml). The combined organic layers were concentrated.

The crude product was mixed with CH ₂ Cl ₂ (200 μl) and TFA (200 μl) and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 2% B, 2-42% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-methoxyethyl)-7-(1H-pyrazol-3-yl)-2Hpyrazolo[4,3-c]quinoline-4-amine (7, 3 mg, 27%). The other regioisomer was also isolated and further purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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-minute hold at 0% B, 0-40% B for 20 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 1-(2methoxyethyl)-7-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-c]quinoline-4-amine, TFA ( 3.8 mg, 9.8%).

Characterization data for 2-(2-methoxyethyl)-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3c]quinoline-4-amine (Example 207): 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.08 (br d, J=1.6 Hz, 1H), 7.87 (br s, 1H), 7.71 (br s, 1H), 7.64 (br d, J=7.9 Hz, 1H ), 7.13-6.95 (m, 2H), 6.75 (br s, 1H), 4.57 (br s, 2H), 3.83-3.79 (m, 2H), 3.25 (s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; feat

- 112 042018 phase B: 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; temperature: 50°C; gradient: 0 to 100% B over 3 min, then hold 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 309.2 [M+H]+; RT: 1.02 min.

Characterization data for 1-(2-methoxyethyl)-7-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3c]quinoline-4-amine (Example 208): 1H NMR (500 MHz, DMSO-d6 ) δ 8.64 (s, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.18 (br s, 1H), 7.97 (br d, J=8.5 Hz, 1H), 7.85 (br s, 1H), 6.86 (d, J=2.2 Hz, 1H), 4.97 (t, J=5.1 Hz, 2H), 3.88 (t, J=5.1 Hz, 2H), 3.18 (s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 to 100% B over 3 min, then hold 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 309.0 [M+H]+; RT: 0.97 min.

Example 209 Preparation of 2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)ethan-1ol

Step 1. 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol5-yl)-2H-pyrazolo[4,3 -c]quinoline-4-amine.

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (80 mg, 0.239 mmol) in DMF (797 µl) cesium carbonate (234 mg, 0.718 mmol) was added followed by (2-bromoethoxy)(tert-butyl)dimethylsilane (56.5 µl, 0.263 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (20 ml) and H2O (20 ml). The aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (24 g RediSep Gold silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ). The second eluting regioisomer was isolated to give 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[ 4,3c]quinoline-4-amine (58.5 mg, 50%). LC-MS m/z 493 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) Shift 8.57 (br s, 1H), 8.18 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.60 (d, J=1.7 Hz, 1H) , 7.37 (br d, J=6.9 Hz, 1H), 7.53-7.07 (m, 2H), 6.52 (d, J=1.8 Hz, 1H), 5.32 (dd, J=10.0, 2.2 Hz, 1H), 4.54 (t, J=4.8 Hz, 2H), 4.08-4.01 (m, 3H), 3.63-3.56 (m, 1H), 2.48-2.36 (m, 1H), 1.99-1.93 (m, 1H), 1.80 (br d, J=12.5 Hz, 1H), 1.64-1.49 (m, 3H), 0.80-0.74 (m, 9H), 0.13 (s, 6H).

Step 2 2-(4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-ethan-1-ol.

To a suspension of 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(1 -(tetrahydro-2H-pyran-2-yl)-1Hpyrazol-5-yl)-2H-pyrazolo[4,3- c]quinoline-4-amine (58 mg, 0.118 mmol) in CH ₂ Cl ₂ (294 μl) TFA (294 μl) was added. The resulting clear orange solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The crude product was dissolved in CH2Cl2 (500 µl) and concentrated.

This product was dissolved in a mixture of CH ₂ Cl ₂ (300 μl) and MeOH (300 μl) and potassium carbonate (81 mg, 0.589 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with EtOAc (20 ml) and saturated aqueous NaHCO ₃ (20 ml). The layers were separated and the organic layer was extracted with 5% MeOH-EtOAc (5x10 ml). The combined organic layers were washed with saturated aqueous NaCl (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in MeOH-CH ₂ Cl ₂ and celite was added. The mixture was concentrated in vacuo, loaded onto a dry run column and purified by flash chromatography (RediSep Gold with 12 g silica gel with 5 g solids cartridge; linear gradient 0-60% MeOH-CH ₂ Cl ₂ ) to give 2-(4-amino -7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)ethan-1-ol (23 mg, 66%) as a white solid. 1Н NMR (400 MHz, DMSO-d ₆ ) δ 13.38-12.79 (m, 1H), 8.49 (s, 1H), 8.07 (br d, J=8.0 Hz, 1H), 7.88 (br s, 1H), 7.83 -7.47 (m, 2H), 7.04-6.83 (m, 2H), 6.75 (br

- 113 042018 s, 1H), 5.04 (t, J=5.3 Hz, 1H), 4.45 (t, J=5.1 Hz, 2H), 3.87 (q, J=5.2 Hz, 2H). Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). m/z 295.0 [M+H]+; RT: 0.62 min.

Example 210 yl)cyclopentan-1-ol

cis-3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-2 Preparation

Step 1. 2-(cis-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-7-(1-(tetrahydro-2H-pyran-2-yl)1H-pyrazol-5-yl)-2H-pyrazolo[ 4,3-c]quinoline-4-amine.

To suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (30 mg, 0.090 mmol), triphenylphosphine (24.71 mg, 0.094 mmol) and trans-3-((tert-butyldimethylsilyl)oxy)cyclopentan-1-ol (20.39 mg, 0.094 mmol) in DMF (897 µl) was added diisopropyl azodicarboxylate (17.66 µl, 0.090 mmol ). The reaction mixture was stirred at 0° C. for 5 minutes, then at room temperature for 17 hours. Additional trans-3((tert-butyldimethylsilyl)oxy)cyclopentan-1-ol (20.39 mg, 0.094 mmol) was added, triphenylphosphine (24.71 mg, 0.094 mmol) and diisopropyl azodicarboxylate (17.66 µl, 0.090 mmol) and stirred at room temperature for 1 h. NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (RediSep gold with 12 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ). The second eluting regioisomer was isolated to give 2-(cis-3((tert-butyldimethylsilyl)oxy)-cyclopentyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)- 2Hpyrazolo[4,3-c]quinoline-4-amine (17.6 mg, 37%). LC-MS m/z 533 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.59 (dd, J=8.1, 1.5 Hz, 2H), 7.31 (dd, J =8.1, 1.6 Hz, 1H), 6.96 (br s, 2H), 6.50 (d, J=1.8 Hz, 1H), 5.30 (dd, J=10.0, 2.0 Hz, 1H), 5.00 (quin, J=7.7 Hz, 1H), 4.41 (quin, J=5.8 Hz, 1H), 4.064.01 (m, 1H), 3.63-3.52 (m, 1H), 2.63-2.55 (m, 1H), 2.47-2.37 (m, 1H), 2.26 (qd, J=7.5, 3.8 Hz, 2H), 2.09-1.92 (m, 3H), 1.88-1.76 (m, 2H), 1.64-1.49 (m, 3H), 0.86 (d, J= 1.0 Hz, 9H), 0.08 (s, 3H), 0.06 (s, 3H).

Step 2 cis-3-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)cyclopentan-1-ol.

To a solution of 2-(cis-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-7-(1-(tetrahydro-2H-pyran-2yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4, 3-c]quinoline-4-amine (17 mg, 0.032 mmol) in CH ₂ Cl ₂ (160 μl) TFA (160 μl) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH ₂ Cl ₂ (300 μl) and concentrated in vacuo.

The crude product was mixed with CH2Cl2 (150 µl) and MeOH (150 µl) and potassium carbonate (22 mg, 0.16 mmol) was added. The suspension was stirred at room temperature for 15 minutes. The reaction mixture was diluted with 1:1 MeOH-CH ₂ Cl ₂ (1 ml), filtered and washed with 1:1 MeOH-CH ₂ Cl ₂ (2x0.5 ml). The filtrate was concentrated in vacuo, then it was mixed with DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 3% B, 3-43% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give cis-3-(4amino-7-(1H-pyrazol-3-yl-2H-pyrazolo[4,3-c]quinolin-2-yl)cyclopentan- 1-ol (6.3 mg, 59%) 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.63 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.88 (s, 1H) , 7.71 (br s, 1H), 7.63 (br d, J=8.5 Hz, 1H), 7.09-6.96 (m, 2H), 6.75 (d, J=1.4 Hz, 1H), 5.04-4.96 (m, 2H ), 4.29-4.24 (m, 1H), 2.32-2.23 (m, 1H), 2.222.14 (m, 1H), 2.01-1.95 (m, 1H), 1.90-1.78 (m, 3H).Analytical LC conditions /MS: column: Waters

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XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/.z 335.2 [M+H]+; RT: 0.87 min.

Compounds of examples 211-246 were prepared according to synthetic procedures similar to those described in examples 207 and 208, 209 or 210 from the corresponding starting compounds of alkyl halide, mesylate or alcohol. The temperature of the alkylation reactions ranged from room temperature to 90° C., and additional equivalents of the alkylating reagent were added in some cases. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). _________________________________________________________________________________

Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 211 H ₂ N \ 2 \u003d N nA ) \u003d/ ^{0 0} O N \u003d / HN ^ 371.1 1.04 δ 13.22-13.01 (m, 1H), 8.92 (s, 1H), 8.21 (d, 7=8.3 Hz, 1H), 8.11 (brs, 1H), 7.92 (br d, 7=6.9 Hz, 1H), 7.88 -7.80 (m, 1H), 6.81 (s, lH), 4.63(t, 7=6.9 Hz, 2H), 3.22-3.17 (m, 2H), 3.00 (s, 3H), 2.422.35 (m, 2H )

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212 τ // o o 371.1 0.951 5 8.63 (s, IH), 8.38 (d, 7=8.5 Hz, IH), 8.19 (brs, IH), 7.99 (brd,7=8.0 Hz, IH), 7.85 (br s, IH), 6.87 (d , 7=2.2 Hz, IH), 4.94 (brt, 7=7.2 Hz, 2H), 3.31-3.24 (m, 3H), 2.97 (s, 4H), 2.35 (quin, 7=7.2 Hz, 2H) 213 /—o z—/ ^z » z^O. ¹ ιτΛ I 378.2 0.67 5 8.64- 8.58 (m, IH), 8.11 (d, 7=8.0 Hz, IH), 7.95 (br s, IH), 7.80 - 7.68 (m, 2H), 6.77 (d, 7=1.9 Hz, IH) , 4.48 (brt, 7=6.7 Hz, 2H), 3.57 (br t, 7=4.3 Hz, 4H), 2.40 - 2.24 (m, 6H), 2.09 (dt, 7=13.5, 6.5 Hz, 2H) 214 nh ₂ ΪΑΠν (AA'N IIX ^N . \ N-XY \__У hn' J 378.2 0.56 5 8.39 (brt,7=7.3Hz, IH), 8.29 (br d, 7=7.7Hz, IH), 8.10-7.99 (m, IH), 7.917.73 (m, 2H), 6.83 (s, IH) , 4.81 (brt,7=6.3 Hz, 2H), 3.54 (br s, 4H), 2.47 - 2.27 (m, 6H), 2.11 -2.02 (m, 2H) 215 I /-and U - GY A o^ I 309.1 1.04 5 8.91 (s, IH), 8.20 (d, 7=8.3 Hz, IH), 8.10 (brs, IH), 7.91 (brd,7=8.0 Hz, IH), 7.887.81 (m, IH), 6.81 ( d, 7=1.9 Hz, IH), 4.85 - 4.72 (m, IH), 4.55 (t, 7=7.0 Hz, 2H), 3.43 (s, 2H), 2.09 (quin, 7=6.5 Hz, 2H) 216 h ₂ n n/Vn ^A° ^h o N=Z HN^ 308.9 1.01 5 8.54 (brs, IH), 8.35 (brd, 7=8.5 Hz, IH), 8.23-8.10 (m, IH), 8.00 - 7.80 (m,2H), 6.86 (s, IH), 4.88 - 4.76 (m , 3H), 3.57-3.50 (m, 2H), 2.09-1.99 (m, 2H) 217 nh ₂ 14P ^N ίι V/ ^he nAA hn' J 295.2 0.86 5 13.26-13.09 (m, IH), 8.64 (s, IH), 8.48 (d, 7=8.8 Hz, IH), 8.19 (brs, IH), 7.96 (br d, 7=8.3 Hz, IH), 7.91 -7.84 (m, IH), 6.86 (s, IH), 5.145.06 (m, IH), 4.86 (brt, 7=5.4 Hz, 2H), 3.93 (br s, 2H)

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218 ^H 2 ^N .^ _N /^/^/OCH3 Ν=< ην^ζ 337.2 1.03 5 8.49 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H), 7.787.68 (m, 1H), 7.64 (br d, 7=7.5 Hz, 1H), 7.13 -6.94 (m, 2H), 6.75 (d, 7=1.9Hz, 1H), 4.43 (t, 7=7.0Hz, 2H), 3.34 (t, 7=6.3Hz, 2H), 3.21 (s, 3H) , 1.95 (quin, 7=7.3 Hz, 2H), 1.54-1.47 (m, 2H) 219 η ₂ ν O Ν=/ ΗΝ^ 337.4 0.99 5 8.28 (s, 1H), 8.17 (d, 7=8.5 Hz, 1H), 8.00 (s, 1H), 7.807.71 (m, 2H), 7.17-7.05 (m, 2H), 6.81 (d, 7 =2.1 Hz, 1H), 4.74 (brt, 7=7.1 Hz, 2H), 3.33 (t, 7=6.3 Hz, 2H), 3.19 (s, 3H), 1.94- 1.87 (m, 2H), 1.59- 1.52 (m, 2H) 220 η ₂ ν V/ Ο Ν=/ ην^) 293.1 1.02 5 8.49 (s, 1H), 8.09 (d, 7=8.1 Hz, 1H), 7.87 (d, 7=1.2 Hz, 1H), 7.71 (s, 1H), 7.64 (brd, 7=7.8 Hz, 1H) , 7.23 - 6.93 (m, 2H), 6.76 (s, 1H), 4.36 (t, 7=6.9 Hz, 2H), 1.95- 1.90 (m, 2H), 0.86 (brt, 7=7.1Hz, ZN) 221 νη ₂ /τ> ||| ^Ν \ / ^CH3 ην' J 293.0 1.00 5 8.28 (s, 1H), 8.16 (brd, 7=8.5 Hz, 1H), 8.00 (brs, 1H), 7.85 - 7.66 (m, 2H), 7.06 (br d, 7=4.4 Hz, 2H), 6.80 (s, 1H), 4.69 (brt, 7=7.2 Hz, 2H), 1.94-1.85 (m, 2H), 0.91 (t, 7=7.3 Hz, ZN) 222 η ₂ ν _n <W^^^ ⁰ ^ch ₃ 4 >=Ν Ο Ν=/^ ΗΝ^ 323.2 1.12 5 8.92 (s, 1H), 8.19 (d, 7=8.3 Hz, 1H), 8.09 (brs, 1H), 7.91 (brd,7=8.5 Hz, 1H), 7.84 (br s, 1H), 6.82 (s , 1H), 4.64 (br t, 7=4.7 Hz, 2H), 3.86 (brt, 7=4.7 Hz, 2H), 3.49-3.44 (m, 2H), 1.07 (t, 7=7.0 Hz, ZN) 223 η ₂ ν \Ζ^... sn ₃ -/Λ ^Ν / Ο Ν=/ ΗΝ^ 323.1 1.21 δ 8.48 (brs, 1H), 8.37 (brd, 7=8.7 Hz, 1H), 8.07 (brs, 1H), 7.86 (brdd, 7=6.4, 1.2 Hz, 1H), 7.80 (brs, 1H), 6.84 ( d, 7=2.2 Hz, 1H), 4.92 (brt, 7=4.8 Hz, 2H), 3.90-3.87 (m, 2H), 3.38 - 3.32 (m, 2H), 0.94 - 0.86 (m, 3H)

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224 nh ₂ hn' J 315.1 0.95 δ 9.01 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.14-8.05 (m, 1H), 7.93 (brd, 7=8.0 Hz, 1H), 7.84 (brs, 1H), 6.82 ( d, 7=1.9 Hz, 1H), 6.70 - 6.43 (m, 1H), 5.11 (td, 7=15.1,2.3 Hz, 2H) 225 I z G ^z \_/ I /----\ ^M ,z Y / 'z o I 315.1 1.00 5 8.73 (s, 1H), 8.44 (d, 7=8.8 Hz, 1H), 8.26-8.16 (m, 1H), 7.97 (brd,7=8.3 Hz, 1H), 7.88 (brd, 7=1.9 Hz, 1H), 6.88 (d, 7=1.9 Hz, 1H), 6.746.49 (m, 1H), 5.44-5.35 (m, 2H) 226 CO T o A ^x 1ΓΑ I 346.3 1.00 5 9.00 (s, 1H), 8.17 (d, 7=8.3 Hz, 1H), 8.05 (brs, 1H), 7.90 (brd,7=8.3 Hz, 1H), 7.81 (br s, 1H), 6.81 (d , 7=1.7 Hz, 1H), 6.27 (s, 1H), 5.80 (s, 2H), 2.38 (s, 3H) 227 nh ₂ ^N ιΓ^\, /T-l to L , ^N /l j T w ^N hn' J 356.1 0.66 5 8.57 (s, 1H), 8.47 (d, 7=4.4 Hz, 1H), 8.43 (d, 7=8.5 Hz, 1H), 8.20 (brs, 1H), 7.99 (br d, 7=8.5 Hz, 1H ), 7.91-7.83 (m, 1H), 7.67 (td, 7=7.6, 1.7 Hz, 1H), 7.25 (d, 7=7.7 Hz, 1H), 7.21 (dd, 7=7.4, 5.2 Hz, 1H) , 6.87 (d, 7=1.7 Hz, 1H), 5.18 (t, 7=7.2 Hz, 2H), 3.423.39 (m, 2H) 228 h ₂ n Y - n/JN \^ ^00H 3 O p=Y HN^ 323.2 0.95 5 13.19 (brs, 1H), 8.62 (s, 1H), 8.35 (d, 7=8.6 Hz, 1H), 8.22 (brs, 1H), 8.00 (brd, 7=7.9 Hz, 1H), 7.89 (br s , 1H), 6.88 (brs, 1H), 4.84 (t, 7=7.0 Hz, 2H), 3.37-3.33 (m, 2H), 3.23 (s, 3H), 2.13 (quin, 7=6.5 Hz, 2H) 229 h ₂ n o ^N \>n Q o N=/ HN^ 335.2 0.96 5 8.92 (s, 1H), 8.19 (d, 7=8.5 Hz, 1H), 8.08 (brs, 1H), 7.91 (brd,7=7.7 Hz, 1H), 7.83 (br s, 1H), 6.82 (s , 1H), 4.624.57 (m, 1H), 4.51-4.45 (m, 1H), 4.33 - 4.26 (m, 1H), 3.78 (q, 7=7.0 Hz, 1H), 3.71 3.65 (m, 1H) , 2.11 -2.00 (m, 1H), 1.88 - 1.75 (m, 2H), 1.71-1.58 (m, 1H)

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230 nh ₂ JOA n-AA / hn' J o— ¹ 335.2 1.09 5 8.70 (s, 1H), 8.09 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.73 7.69 (m, 1H), 7.66 - 7.62 (m, 1H), 6.75 (s, 1H) , 5.73 (dd, 7=8.7.3.2 Hz, 1H), 4.O1 (brd, 7=11.0 Hz, 1H), 3.79-3.72 (m, 1H), 3.58-3.53 (m, 2H), 2.03-1.95 (m, 1H), 1.821.70 (m, 1H), 1.65 - 1.57 (m, 2H) 231 h ₂ n kA P ^H 3 N Λ rN pun=A Hn'A 363.9 0.93 5 8.72- 8.65 (m, 1H), 8.46 (d,7=8.5 Hz, 1H), 8.20 (brs, 1H), 7.95 (br d, 7=8.3 Hz, 1H), 7.87 (brs, 1H), 6.87 (d, 7=2.1 Hz, 1H), 5.07-5.00 (m, 1H), 4.99 - 4.93 (m, 1H), 4.32-4.21 (m, 1H), 3.943.85 (m, 1H), 3.64-3.54 (m, 2H), 3.27 (br d, 7=9.5 Hz, 1H), 3.03 -2.86 (m, 2H), 2.79 (br s, 3H) 232 £o A z / z > tA ъ z I 323.3 1.01 5 8.58 (brs, 1H), 8.41 (d, 7=8.5 Hz, 1H), 8.18 (brs, 1H), 7.94 (br dd, 7=5.8, 3.9 Hz, 1H), 7.89-7.78 (m, 1H) , 6.87 (s, 1H), 4.98-4.91 (m, 2H), 4.48 (dd, 7=14.3, 9.4 Hz, 1H), 2.29-2.20 (m, 1H), 0.86 (d, 7=6.6 Hz, ZN ); two CH protons are not visible, probably due to overlap with the suppressed water peak. 233 h ₂ n AAn WJ^O O N=/ hn'A 339.2 0.73 5 8.61 (s, 1Н), 8.45 (brd, 7=8.8 Hz, 1Н), 8.15 (brs, 1Н), 7.96 (br d, 7=8.3 Hz, 1Н), 7.84 (brs, 1Н), 6.86 (s , 1Н), 4.95 (brt, 7=5.2 Hz, 2Н), 3.96 (brt, 7=5.1 Hz, 2Н), 3.39 -3.36 (m, 2Н), 3.34 (br d, 7=4.7 Hz, 2Н) 234 A 7~z ^Ζ ^ζ-Ο^ ¹ 1ΓΑ ^Z A I 325.1 0.68 5 8.92 (s, 1H), 8.20 (d,7=8.2 Hz, 1H), 8.11 (brs, 1H), 7.92 (brd,7=7.6 Hz, 1H), 7.86 (br s, 1H), 6.82 (s , 1Н), 5.31 (br d, 7=5.0 Hz, 1Н), 4.98 (brs, 1Н), 4.60 (br d, 7=13.7 Hz, 1Н), 4.35 (dd, 7=13.5, 8.7 Hz, 1Н) , 3.94 (brs, 1H)

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235 τ ζ Q \ / I / \ ^Μ ,ζ Γ -Ζ. ι'ο Ο ι Τ 325.1 0.64 5 8.62 (s, 1H), 8.52 (d, 7=8.6 Hz, 1H), 8.17 (brs, 1H), 7.94 (brd,7=8.5 Hz, 1H), 7.85 (br s, 1H), 6.87 (d , 7=1.7 Hz, 1H), 5.26 (br d, 7=0.6 Hz, 1H), 5.14-5.00 (m, 1H), 4.90-4.81 (m, 1H), 4.78 4.71 (m, 1H), 4.02 ( br d, 7=1.6 Hz, 1H) 236 νη ₂ ϊ £Ν-Ο ΗΝ ^Ζ J 335.1 0.97 5 13.10-12.78 (m, 1H), 8.58 (s, 1H), 8.09 (d, 7=8.0 Hz, 1H), 7.88 (brs, 1H), 7.837.58 (m, 2H), 7.08-6.91 (m , 2H), 6.75 (d, 7=1.5 Hz, 1H), 4.77 - 4.69 (m, 1H), 4.02 (br dd, 7=11.0, 2.9 Hz, 2H), 2.18 -2.12(m, 2H), 2.11 -2.01 (m, 2H); four CH protons are not visible, probably due to overlap with the suppressed water peak. 237 νη ₂ ^Ν ην' Τ 321.1 0.89 5 13.42-13.09 (br, 1Н), 9.68 - 9.47 (br, 1Н), 9.03 (s, 1Н), 9.13-8.92 (br, 1Н), 8.21 (d, 7=8.2 Hz, 1Н), 8.13 (brs , 1Н), 7.93 (brd, 7=8.3 Hz, 1Н), 7.91 -7.86 (br, 1Н), 6.83 (s, 1Н), 5.47 (td, 7=5.4, 2.9 Hz, 1Н), 4.16 -4.06 ( w, 3H), 3.92 (td, 7=8.5, 5.4 Hz, 1H), 2.65 - 2.56 (w, 1H), 2.40 - 2.33 (w, 1H) 238 νη ₂ ГШ7 ιΑι ^ν ΗΝ e enantiomer 1 321.3 1.04 δ 8.56 (s, 1Н), 8.08 (d,7=8.0 Hz, 1Н), 7.86 (s, 1Н), 7.73 7.67 (br, 1Н), 7.64 - 7.60 (br, 1Н), 6.91 -6.79 (br, 2Н), 6.74 (s, 1Н), 5.36–5.31 (br, 1Н), 4.13–4.03 (br, ЗН), 3.93–3.85 (br, 1Н), 2.60–2.54 (br, 1Н), 2.38–2.30 ( w, 1H) 239 νη ₂ ϊ ^Ν ΗΝ ^enantiome R 2 321.3 1.04 δ 8.57 (s, 1H), 8.08 (d,7=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (br s, 1H), 7.62 (brd,7=8.5 Hz, 1H), 6.91 -6.80 (br, 2H), 6.74 (s, 1H), 5.36-5.32 (br, 1H), 4.13-4.04 (br, 3H), 3.92-3.86 (br, 1H), 2.602.53 (br, 1H), 2.34 (br dd, 7=9.2, 5.4 Hz, 1H)

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240 nh ₂ JOA ⁿ jtj Ά Ν^Α^ /V HN / \ J 321.1 1.03 δ 8.68 - 8.62 (m, 1H), 8.45 (brd,7=8.8Hz, 1H), 8.20(br s, 1H), 8.00 (brd,7=8.5Hz, 1H), 7.91-7.83 (m, 1H) , 6.88 (br d, 7=2.2 Hz, 1H), 5.97-5.89 (m, 1H), 4.25 4.17 (m, 2H), 4.07-4.01 (m, 1H), 3.99-3.92 (m, 1H), 2.63 -2.56 (m, 1H), 2.552.52 (m, 1H) 241 νη ₂ Αρ ^Ν ν^Α^ ην' J 307.2 0.84 δ 8.82 (s, 1H), 8.21 (d, 7=8.2 Hz, 1H), 7.99 (br s, 1H), 7.79 (brd,7=8.2 Hz, 2H), 6.80 (d, 7=2.1 Hz, 1H ), 5.92 (quin, 7=6.7 Hz, 1H), 5.08-5.04 (m, 2H), 5.03 - 5.00 (m, 2H) 242 ΞΕ Ζ Q μ \ / ΞΕ )-------( ¹⁴⁵ /X___.ζ A 307.1 0.98 6 8.76 (s, 1H), 8.19 (brd, 7=8.5 Hz, 2H), 7.97 (br d, 7=8.8 Hz, 1H), 7.88 (brs, 1H), 6.86 (d, 7=2.1 Hz, 1H ), 6.39 (quin, 7=6.2 Hz, 1H), 5.20-5.17 (m, 2H), 5.155.11 (m, 2H) 243 ΞΕ , ^ζ -ζ: Αί * ?=? V ο I CO 347.0 0.78 δ 8.67 (s, 1H), 8.04 (d, 7=8.0 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.63 (brd, 7=8.0 Hz, 1H), 7.13-6.98 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H), 6.03 (s, 2H), 2.48 (s, 3H) 244 η ₂ ν Κ/ν ^Ν \ V-Ν , ^Ν 'Ν /=/ ⁴ -X < \ O^CH ₃ Ν=/ ην^ 347.1 0.80 δ 8.68 (s, 1H), 8.36 (d, 7=8.5 Hz, 1H), 8.18 (brs, 1H), 7.95 (brd,7=8.8 Hz, 1H), 7.84 (br s, 1H), 6.88 (d , 7=1.7 Hz, 1H), 6.37 (s, 2H), 2.45 (s, 3H) 245 f ₃ C nVn> ^0H χΥ ^Ν ην' J 363.2 1.00 δ 8.64 (brs, 1H), 8.12 (d, 7=8.2 Hz, 1H), 7.92 (brs, 1H), 7.79 - 7.66 (m, 2H), 7.04-6.91 (m, 1H), 6.77 (d, 7=1.6 Hz, 1H), 4.76-4.69 (m, 1H), 4.62 - 4.54 (m, 2H) 246 Η ₂ Ν / \ \—(Α ⁴ Ν' O C Η ₃ ^Ν \)=ν Ο Ν=/ ην'Υ 349.1 1.13 δ 8.56 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.71 (br s, 1H), 7.63 (brd,7=8.3 Hz, 1H), 7.12-6.91 (m, 2H), 6.75 (d, 7=1.7 Hz, 1H), 5.14 5.07 (m, 1H), 4.11-4.06 (m, 1H), 3.25 (s, 3H), 2.38-2.25 (m, 3H) , 2.20-2.12 (m, 1H), 2.08-1.99 (m, 1H), 1.84 1.74 (m, 1H)

Examples 238 and 239.

The racemic product, Example 237, was prepared from the respective starting compounds and purified by preparative chiral SFC using the following conditions to give Example 238 and Example 239 as separate undetermined isomers: Instrument: Waters 100 Prep SFC; column: Chiral AD, 30x250 mm, 5 µm; mobile phase: 80% CO2/20% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Compound of Example 238 (first eluting isomer), retention time: 25.73 min. Example 239 compound (second desired isomer). Retention time: 30.37 min.

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Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiralpak AD, 4.6x100 mm, 5 microns; mobile phase: 80% CO2/20% IPA with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 238 (first eluting isomer), retention time: 11.4 min. Example 239 compound (second eluting isomer). Retention time: 13.3 min.

Example 247 Preparation of 2-(2-methoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4amine

A mixture of 7-bromo-2-(2-methoxyethyl)-2H-pyrazolo[4,3-c]quinoline-4-amine (33 mg, 0.103 mmol), 1Hpyrazole (10.49 mg, 0.154 mmol) and sodium carbonate ( 43.6 mg, 0.411 mmol) was evacuated and refilled with N ₂ , then DMSO (1027 μl) was added. The resulting mixture was purged with N ₂ for 10 min, then N,N'-dimethylethylenediamine (33.2 μl, 0.308 mmol) and copper(I) iodide (29.4 mg, 0.154 mmol) were added.

The mixture was purged with N ₂ for 1 min, then sealed and stirred at 120° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H ₂ O (20 ml), 1:1 N ₂ O-aq. NH ₄ OH (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: Xbridge C18, 200x19 mm, particles 5 μm; 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 min hold at 3% B, 3-43% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-methoxyethyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine ( 17.4 mg, 52%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.52 (d, J=2.2 Hz, 1H), 8.51 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.85 (d, J= 2.2 Hz, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.67 (dd, J=8.4, 2.1 Hz, 1H), 7.10-7.00 (m, 2H), 6.55 (s, 1H), 4.57 ( t, J=5.0 Hz, 2H), 3.81 (t, J=5.0 Hz, 2H), 3.25 (s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 308.9 [M+H]+; RT: 1.13 min.

Example 248 Preparation of 2-(2-methoxyethyl)-7-(thiophen-2-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine

A mixture of 7-bromo-2-(2-methoxyethyl)-2H-pyrazolo[4,3-c]quinoline-4-amine (33 mg, 0.103 mmol), 4,4,5,5tetramethyl-2-(thiophene-2 -yl)-1,3,2-dioxaborolane (32.4 mg, 0.154 mmol) and tribasic potassium phosphate (65.4 mg, 0.308 mmol) were evacuated and filled with N ₂ again, then 1,4-dioxane (428 μl) was added ) and H ₂ O (86 μl). The resulting mixture was purged with N ₂ for 15 min, then chlorine(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl) was added ]palladium(II) (2.021 mg, 2.57 µmol). The mixture was purged with N2 for 1 min, then sealed and stirred at 100°C for 20 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml) and washed with H2O (20 ml). The aqueous layer was extracted with EtOAc (20 ml) and the combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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 min hold at 14% B, 14-54% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(2-methoxyethyl)-7-(thiophen-2-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine (26, 9 mg, 81%). 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.51 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.55 (d, J=3.7 Hz, 1H), 7.54

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7.50 (m, 2H), 7.15 (dd, J=5.0, 3.7 Hz, 1H), 7.21-7.05 (m, 2H), 4.56 (t, J=4.9 Hz, 2H), 3.82-3.79 (m, 2H) , 3.24(s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm. m/z: 325.2 [M+H]+; RT: 1.28 min.

Examples 249 and 250 Preparation of 2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)ethan-1-ol and 2-(4- amino-7-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1-yl)ethan-1-ol.

Step 1 N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine.

A mixture of 7-bromo-N,2-bis(4-methoxybenzyl)-2H-pyrazolo[4,3-c]quinoline-4-amine (102 mg, 0.203 mmol), 1H-pyrazole (20.69 mg, 0.304 mmol ) and sodium carbonate (86 mg, 0.810 mmol) was evacuated and filled with N ₂ again, then DMSO (2026 μl) was added. The resulting mixture was purged with N2 for 10 min, then N,N'-dimethylethylenediamine (65.4 µl, 0.608 mmol) and copper(I) iodide (57.9 mg, 0.304 mmol) were added. The mixture was purged with N2 for 1 min, then sealed and stirred at 120°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml), washed with H2O (20 ml), 1:1 H ₂ O- aq. NH ₄ OH (20 ml) and saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-100% EtOAc-CH ₂ Cl ₂ ) to give N,2-6uc(4methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4 ,3-c]quinoline-4-amine (83.5 mg, 84%) as a white solid. LC-MS m/z 491 [M+H] ⁺ ; 1Н NMR (400 MHz, DMSO-d ₆ ) δ 8.61 (d, J=2.1 Hz, 1H), 8.47 (s, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.95 (br t, J= 5.3 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.69 (dd, J=8.5, 2.2 Hz, 1H), 7.35 (d, J= 7.8 Hz, 4H), 6.99-6.94 (m, 2H), 6.91-6.85 (m, 2H), 6.55-6.53 (m, 1H), 5.57 (s, 2H), 4.71 (d, J=5.6 Hz, 2H ), 3.74 (s, 3H), 3.71 (s, 3H).

Step 2. 7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine, TFA.

Solution of N,2-bis(4-methoxybenzyl)-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine (82.5 mg, 0.168 mmol) in TFA (336 μl) was sealed and stirred at 70°C for 18 h, then cooled to room temperature and concentrated in vacuo. The crude product was concentrated from CH ₂ Cl ₂ (4x2 ml). The crude product was triturated with CH ₂ Cl ₂ mixing it with CH ₂ Cl ₂ (1 ml), filtered and then washed with CH ₂ Cl ₂ (3x1 ml) to give 7-(1H-pyrazol-1-yl)-2H-pyrazolo [4,3c]quinoline-4-amine, TFA (52.8 mg, 86%) as an off-white solid. LC-MS m/z 251 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.35-13.08 (m, 1H), 9.78-9.51 (m, 1H), 8.88-8.59 (m, 3H), 8.34 (br d, J=7.4 Hz, 1H), 8.25 (br s, 1H), 8.13–8.00 (m, 1H), 7.88 (br s, 1H), 6.66 (br s, 1H).

Step 3. 2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)ethan-1-ol and 2-(4-amino7 -(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1-yl)ethan-1-ol.

Cesium carbonate was added to a suspension of 7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine, TFA (26 mg, 0.071 mmol) in DMF (238 µl) at room temperature (69.8 mg, 0.214 mmol) followed by 2-bromoethan-1-ol (5.56 µl, 0.079 mmol). The suspension was stirred at room temperature for 18 h and at 50°C for 6 h. The reaction mixture was diluted with H ₂ O (2 ml) and was extracted with EtOAc (3x2

- 123 042018 ml). The combined organic layers were concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 μm; 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-minute hold at 0% B, 0-40% B for 25 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(4-amino-7-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1-yl)ethane1 -ola, TFA (4.1 mg, 14%). The other regioisomer was also isolated and further purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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-minute hold at 0% B, 0-40% B for 25 min, then 5-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(4-amino-7-(1H-pyrazol-1-yl)2H-pyrazolo[4,3-c]quinolin-2-yl)ethan- 1-ol, TFA (4 mg, 13%).

Characterization data for 2-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)ethan-1-ol (Example 249): ¹ H NMR ( 500 MHz, DMSOA) δ 8.80 (s, 1H), 8.57 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.86 (br d, J=9.1 Hz, 1H ), 7.82 (s, 1H), 6.60 (s, 1H), 5.16 (br d, J=1.9 Hz, 1H), 4.50 (br t, J=5.0 Hz, 2H), 3.88 (br s, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). mz 295.1 [M+H]+; RT: 0.81 min.

Characterization data for 2-(4-amino-7-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1yl)ethan-1-ol (Example 250): 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.68-8.64 (m, 1H), 8.62 (s, 1H), 8.54 (d, J=9.0 Hz, 1H), 8.22 (br s, 1H), 7.98 (dd, J= 8.8, 1.3 Hz, 1H), 7.87 (d, J=1.0 Hz, 1H), 6.66 (d, J=1.7 Hz, 1H), 5.19-5.07 (m, 1H), 4.86 (br t, J=5.1 Hz , 2Н), 3.93 (br t, J=4.8 Hz, 2Н). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 295.2 [M+H]+; RT: 0.97 min.

Examples 251 and 252 Preparation of 3-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)propan-1-ol and 3-(4- amino-7-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1-yl)propan-1-ol.

Cs ₂ CO ₃ , DMF, rt;

TFA

CH ₂ CI ₂ , rt;

_{K2CO3 _}

CH ₂ CI ₂ , MeOH

Cesium carbonate was added to a suspension of 7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine, TFA (26 mg, 0.071 mmol) in DMF (238 µl) at room temperature (69.8 mg, 0.214 mmol) followed by (3-bromopropoxy)(tert-butyl)dimethylsilane (18.19 µl, 0.079 mmol). The suspension was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O (2 ml) and extracted with EtOAc (3x2 ml). The combined organic layers were concentrated in vacuo.

The crude product was dissolved in CH ₂ Cl ₂ (150 μl) and TFA (150 μl) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude product was concentrated from CH2Cl2 (300 µl).

The crude product was mixed with CH ₂ Cl ₂ (150 μl) and MeOH (150 μl) and potassium carbonate (49 mg, 0.36 mmol) was added. The suspension was stirred at room temperature for 15 minutes. The reaction mixture was diluted 1:1 MeOH-CH ₂ Cl ₂ (1 ml) and filtered (filter pipette). The filtrate was concentrated in vacuo, then mixed with DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5

- 124 042018 microns; 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 min hold at 1% B, 1-41% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. Each product was further purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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 minute hold at 0% B, 0-20% B for 25 minutes, then 5 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 3-(4-amino-7-(1Hpyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)propan-1 -ol, TFA (12.2 mg, 41%) and 3-(4-amino-7-(1Hpyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1-yl)propan-1 -ola, TFA (4.1 mg, 14%).

Characterization data for 3-(4-amino-7-(1H-pyrazol-1-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)propan-1-ol (Example 251): 1H NMR (500 MHz, DMSO-d6) δ 8.90-8.88 (m, 1H), 8.61-8.57 (m, 1H), 8.26 (d, J=8.7 Hz, 1H), 8.15-8.12 (m, 1H), 7.95 (br d , J=8.2 Hz, 1H), 7.84 (s, 1H), 6.63 (s, 1H), 4.91-4.75 (m, 1H), 4.54 (br t, J=7.0 Hz, 2H), 3.45 (br t, J=6.0 Hz, 2H), 2.08 (quin, J=6.4 Hz, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 309.1 [M+H]+, RT: 0.83 min.

Characterization data for 3-(4-amino-7-(1H-pyrazol-1-yl)-1H-pyrazolo[4,3-c]quinolin-1yl)propan-1-ol (Example 252): 1H NMR (500 MHz, DMSO-d ₆ ) 5 8.68 (d, J=2.4Hz, 1H), 8.62 (s, 1H), 8.46 (d, J=9.0Hz, 1H), 8.26 (d, J=1.9Hz, 1H) , 8.04 (dd, J=8.9, 1.7 Hz, 1H), 7.88 (s, 1H), 6.66 (s, 1H), 4.85 (br t, J=7.2 Hz, 2H), 3.55-3.51 (m, 2H) , 2.10-2.02 (m, 2H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 309.2 [M+H] ⁺ ; RT: 0.75 min.

Example 253 Preparation of 2-[4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl]propan-1ol.

Step 1. Synthesis of ethyl 2-[4-amino-7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H-pyrazolo[4,3-c]quinolin2-yl]propanoate.

7-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-2H-pyrazolo[4,3-c]quinoline-4-amine (100 mg, 0.299 mmol, 1 eq.), Cs ₂ CO ₃ (292 mg, 0.89 mmol, 3 eq.), DMF (5 ml), ethyl 2-bromopropanoate (64.9 mg, 0.36 mmol, 1.2 eq.) . The resulting solution was stirred for 2 hours at 65°C. The residue was dissolved in 15 ml H2O. The resulting solution was extracted with 2x15 ml of ethyl acetate and concentrated. This resulted in 100 mg (77%) of ethyl 2-[4-amino-7-[1-(oxan-2-yl)-1Hpyrazol-5-yl]-2H-pyrazolo[4,3-c]quinolin- 2-yl]propanoate as a yellow solid. LCMS: (ES, m/z): [M+H] ⁺ =435.5.

Step 2. Synthesis of ethyl 2-[4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2yl]propanoate.

Ethyl 2-[4-amino-7-[1-(oxan-2-yl)-1H-pyrazol-5yl]-2H-pyrazolo[4,3-c]quinolin-2-yl ]propanoate (100 mg, 0.23 mmol, 1 eq.), DCM (10 ml), HCl in dioxane (0.5 ml, 16.4 mmol, 71.5 eq.). The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was concentrated. This resulted in 60 mg (74%) ethyl 2-[4-amino-7

- 125 042018 (1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl]propanoate in the form of a yellow yellow substance. LC-MS: (ES, m/z): [M+H]+=351.4.

Stage 3. Synthesis of 2-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)propan-1-ol.

Ethyl 2-[4-amino-7-(1H-pyrazol-5-yl)-2Hpyrazolo[4,3-c]quinolin-2-yl]propanoate (60 mg, 0.171 mmol, 1 eq.), MeOH (10 ml), NaBH4 (16.20 mg, 0.428 mmol, 2.5 eq.). The resulting solution was stirred for 2 h at 0°C. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: Sunfire Prep C18 OBD column, 10 µm, 19x250 mm; mobile phase, water (0.05% TFA) and ACN (15% PhaseB to 25% in 9 min); detector, 254/210 nm. This resulted in 20 mg (27%) of 2-(4-amino-7-(1H-pyrazol5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)propan-1-ol as white solid. LC-MS: (ES, m/z): [M+H]+=309.2. ¹ H NMR (400 MHz, methanol^) δ 8.82 (s, 1H), 8.36-8.34 (d, J=8.0 Hz, 1H), 8.02-8.01 (m, 1H), 7.95-7.93 (m, 1H), 7.77-7.76 (d, J=2.4 Hz, 1H), 6.83-6.82 (d, J=2.4 Hz, 1H), 4.87-4.74 (m, 1H), 3.98-3.93 (m, 2H), 1.69-1.68 ( d, J=6.8 Hz, 3H).

The compounds of examples 254-285 were prepared according to synthetic procedures similar to those described in examples 150, 151, 209 or 253 from the corresponding starting compounds. Analytical LC/MS conditions.

A: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

B: column: Shim-pack XR-ODS, 3.0x50 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 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

C: column: Kinetex EVO C18, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

D: column: Kinetex XB-C18, 2.1x30 mm, particles 1.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 35% B over 1.7 min, then to 100% over 0.5 min, then hold 0.6 min at 100% B; flow rate: 1 ml/min; detection: MS and UV. E: Column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 0 to 30% B over 3 min, then to 95% over 0.2 min, then 1.0 min hold at 95% B; flow rate: 1 ml/min; detection: MS and UV.

F: column: XSelect HSS T3, 4.6x100 mm, particles 3.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 10 to 95% B over 6.0 min, then hold 2.0 min at 100% B; flow rate: 1.5 ml/min; detection: UV.

G: column: Ascentis Express C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 95% B over 2.0 min, then hold 0.7 min at 95% B; flow rate: 1.5 ml/min; detection: MS and UV.

H: column: Shim-pack XR-ODS, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 50% over 3 minutes, then to 95% B over 0.3 minutes, then hold 0.4 minutes at 95% B; flow rate: 1 ml/min; detection: MS and UV.

I: column: Shim-pack XR-ODS, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 40% over 3 min, then to 100% B over 0.3 min, then hold 0.4 min at 95% B; flow rate: 1.2 ml/min; detection: MS and UV.

J: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 95% B over 3.2 min, then hold 1.0 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

K: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 40% B in 3.0 min, then to 95% B in 0.2 min, then 1.0 min hold at 95% B; flow rate: 1 ml/min; detection: MS and UV.

L: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 95% B over 1.7 min, then 1.0 min hold at 95% B; flow rate: 1 ml/min; detection: MS and UV.

M: column: Titan C18, 2.1x50 mm, particles 1.9 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 50% over 2.2 min, then to 100% B over 0.8 min, then hold 0.8 min at 95% B; flow rate: 0.7 ml/min; detection: MS and UV.

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N: column: Ascentis Express C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 100% B over 2.0 min, then hold 0.8 min at 95% B; flow rate: 1.5 ml/min; detection: MS and UV.

A: Column: Kinetex XB-C18, 2.1x30 mm, particles 1.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 100% B over 0.8 min, then hold 0.5 min at 100% B; flow rate: 1 ml/min; detection: MS and UV

Etc. No. Structure LC/MS [M+H]+ RT (min)/ LC condition Ή NMR, unless otherwise noted, 400 MHz, Mstanol-sat 254 H ₂ N Άν _n g γ Υν ⁿ z ^s O O ΗΝ-/ 350.3 1.15/D δ 8.41 (s, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.71 (s, 2H), 6.77 (d, J = 2.2 Hz, 1H), 4.61-4.45 ( m, 2H), 1.93 (s, 3H), 1.26 (d, J= 6.2 Hz, 3H) 255 m Y \ / t ) ( u ABOUT z Lz 350.4 2.58/E δ 8.45 (s, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.72 (s, 2H), 6.77 (d, J = 2.2 Hz, 1H), 4.49 (dd, J = 13.9, 5.5 Hz, 1H), 4.42 (dd, J = 13.9, 7.1 Hz, 1H), 3.87 (dd, J = 10.8, 2.6 Hz, 1H), 3.79 (dt, J = 11.4, 3.2 Hz, 1H ), 3.64 3.52 (m, 1H), 3.48 - 3.34 (m, 2H), 2.95 (m, 2H) 256 schs 1 L. l - θ ^Η 3 A / L O ⁿ yj 364.0 1.16/A δ 8.31 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.71 (s, 2H), 6.76 (s, 1H), 4.83 (s, 2H), 1.99 ( s, 3H), 1.43 (s, 6H) 257 H ₃ C and χΥ ^Ν Μ 308.2 2.20/F Ή NMR (400 MHz, DMSOd ₆ ) δ 8.97 (s, 1H), 8.28-8.13 (m, 2H), 7.98-7.87 (m, 2H), 6.85 (d, J = 2.4 Hz, 1H), 4.74-4.64 ( _m , 2H), 3.88 (s, 1H), 1.28 (d,J=6.7 Hz, 3H)

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258 Y ² O ^ CH3 ι n ^- ⁷ ΝχΛΛ m 376.2 0.88/G Ή NMR (300 MHz, Mstanol-όΛ) δ 8.70 (s, 1H), 8.34-8.32 (m, 1H), 8.01 (s, 1H), 7.96-7.93 (m, 1H), 7.777.76 (m, 1H ), 6.83-6.82 (d, J = 2.3 Hz, 1H), 4.70-4.63 (m, 2H), 4.57-4.51 (m, 1H), 3.583.45 (m, 2H), 2.10 (s, 3H), 2.08-2.07 (m, 2H), 1.90-1.86 (m, 2H) 259 H ₂ N ^O< uCH ₃ Ν 0 \u003d ν CH3 O HN- / ^ ^N X / 350.2 1.92/H 5 8.74-8.72 (5.7=8.5Hz, 1H), 8.33-8.31 (d, J= 8.2Hz, 1H), 8.01-8.00 (m, 1H), 7.997.96 (m, 1H), 7.77-7.76 (m, 1H), 6.83-6.82 (m, 1H), 4.784.67 (m, 2H), 4.07-3.94 (m, 2H), 3.0l(s, 2H), 2.94 (s, 1H), 2.03- 2.02 (d, 7= 4.4Hz, 2H), 1.73 (s, 1H) 260 h ₂ n n)=n o HN-/ 364.2 1.01/B 5 8.86 (s, 1H), 8.34-8.32 (d,7 = 8.3 Hz, 1H), 8.03-8.02 (m, 1H), 7.97-7.95 (m, 1H), 7.787.77 (d, 7=2.4 Hz , 1H), 6.83-6.82 (d, 7= 2.4 Hz, 1H), 4.87 (m, 2H), 3.83 (s, 4H), 3.49-3.47 (m, 2H), 3.08 (s, 4H) 261 h ₂ n ch ₃ )—y ^X N^^N _s N \= _N 'CH ₃ O HN -/ N^ 322.2 1.71/1 5 8.93 (s, 1H), 8.42-8.40 (d,7 = 8.3 Hz, 1H), 8.06-8.05 (m, 1H), 8.00-7.97 (m, 1H), 7.807.79 (d, 7=2.4 Hz , 1H), 6.87-6.86 (d, 7= 2.4 Hz, 1H), 5.04-5.02 (t, 7= 5.8 Hz, 2H), 3.94-3.91 (t, 7= 5.8 Hz, 2H), 3.10 (s, 6H) 262 nh ₂ ch ₃ νΛ\ L\ ⁿ U 1 I / ^N — //—\ J /4<*N 0 H /j 420.0 1.62/J Ή NMR (400 MHz, DMSO7 ₆ ) δ 13.34 - 12.88 (s, 1H), 8.39 (s, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.88 - 7.55 (m, 3H), 7.49 (s , 1H), 6.97 - 6.94 (m, 2H), 6.76 (s, 1H), 4.70 (s, 2H), 4.19-4.15 (m, 1H), 3.80-3.70 (m, 2H), 2.122.08 (m , 1H), 2.08- 1.90 (m, 1H), 1.81- 1.64 (m, 2H), 1.38 (d,7= 10.5 Hz, 6H) 263 H ₂ N 0 ^CH3 μ V O HN-/^ n^ 378.5 2.47/1 Ή NMR (300 MHz, Methanol-7 ₄ ) δ 8.46 (s, 1Н), 8.24 (d,7= 8.2 Hz, 1H), 7.92 (s, 1H), 7.70 (s, 2H), 6.76 (d, J = 2.2 Hz, 1H), 4.77 - 4.56 (m, 2H), 3.77 (t, 7= 4.9 Hz, 2H), 3.63 (dd, 7 = 11.6, 3.0 Hz, 1H), 3.50 - 3.34 (m, 1H) ,

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3.24 (s,lH), 2.99 - 2.84 (m, 2H), 2.81 - 2.66 (m, 1H), 2.57 (dd, J = 12.4, 4.6 Hz, 1H), 1.18 (t, J= 7.2 Hz, 3H) 264 n ₃ s 0, L-CH ₃ η ₂ ν and o HN—/ 438.0 1.28/A Ή NMR (400 MHz, DMSOd ₆ ) δ 13.28 (d, J = 200.7 Hz, 1H), 10.50 (s, 1H), 8.68 (s, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.28 ( s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 6.89 (d, J = 2.2 Hz, 1H), 4.68 (d, J= 39.7 Hz, 2H), 3.95 (d, J = 12.0 Hz, 1H), 3.83 (d, J = 12.0 Hz, 1H), 3.74 (s, 1H), 3.54 (dt, J = 36.0, 10.7 Hz, 2H), 3.19 (d, J = 13.0 Hz, 1H), 3.01 (s, 1H), 1.70 (d, J = 21.8 Hz, 6H) 265 h ₂ n γ \ ^N . \=N OCH ₃ O HN-Z 392.3 1.94/K δ 8.92 (s, 1H), 8.37-8.34 (d, J = 8.3 Hz, 1H), 8.01-7.97 (m, 2H), 7.78-7.77 (d, J= 2.4 Hz, 1H), 6.85-6.84 (d , 7=2.4 Hz, 1H), 5.03-4.93 (m, 2H), 3.933.59 (m, 5H), 3.50 (s, 3H), 3.48-3.36 (m, 2H), 2.24-2.14 (m, 2H ), 2.07-1.93 (m, 2H) 266 h ₂ n y - \ . _| /γ^N'' ⁴ ^ ^N ^/'~00Η3 0 hn-Q n'^ 378.2 1.05/B δ 8.89 (s, 1H), 8.36-8.34 (d, 7 = 8.2 Hz, 1H), 8.03-8.02 (m, 1H), 7.98-7.95 (m, 1H), 7.787.77 (d, J = 2.4 Hz , 1H), 6.84-6.83 (d, 7= 2.4 Hz, 1H), 4.98-4.96 (m, 2H), 4.19 (s, 1H), 3.81 (s, 4H), 3.48 (s, 3H), 3.13- 3.12 (m, 2H), 2.21 (s, 2H) 267 n g 9 ^Nc AQQh, 1 N—' ^H 322.0 1.03/L Ή NMR (300 MHz, Methanol-7 ₄ ) δ 8.90 (s, 1H), 8.40 (d,7= 8.3 Hz, 1H), 8.04 - 7.94 (m, 2H), 7.77 (d, J = 2.4 Hz, 1H ), 6.85 (d, 7= 2.4 Hz, 1H), 4.75 (s, 2H), 1.45 (s, 6H) 268 ^^OCH ₃ ^H2N v^n^ ⁿ ^ AH HN~Z nJ* 364.2 1.02/B δ 8.85 (s, 1H), 8.40-8.38 (d, J = 8.3 Hz, 1H), 8.05-8.04 (m, 1H), 7.98-7.96 (m, 1H), 7.787.77 (d, J = 2.4 Hz , 1H), 6.84-6.83 (d, 7= 2.4 Hz, 1H), 4.96-4.84 (m, 2H), 4.66-4.65 (m, 2H), 4.38-4.36 (m, 1H), 4.11-4.03 (m , 2H), 3.89-3.86 (m, 2H), 3.45 (s, 3H)

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269 H ₂ N ° ^SN z Co and w HN-P 392.4 1.06/A Ή NMR (400 MHz, DMSOd ₆ ) δ 13.12 (d, J = 184.9 Hz, 1H), 8.45 (s, 1H), 8.07 (d, J= 7.9 Hz, 1H), 7.94 - 7.43 (m, 3H), 6.91 (s, 2H), 6.77 (s, 1H), 5.02 - 4.92 (m, 2H), 4.66 - 4.56 (m, 0.6H), 4.35 4.18 (m, 0.7H), 4.10 - 3.99 (m, 0.7H ), 3.77 - 3.59 (m, 2H), 3.47 (d, J= 8.8 Hz, 2H), 3.39 (d, J = 12.6 Hz, 1H), 3.23 - 3.12 (m, 0.4H), 2.10 1.51 (m, 3H) 270 Η ₂ Ν NC /—Ρ'Ν'^ΧχΝ _χ 3-- ^ΟΗ 3 Ρ=" H ₃ c Γ CH, ρ ΗΝ-Ζ Ν'Ρ 403.3 1.21/Α Ή NMR (400 MHz, DMSOd ₆ ) δ12.88 (s, 1H), 8.39 (s, 1H), 8.16 (d, J= 8.0 Hz, 1H), 8.06 (d, 7=8.5 Hz, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 7.65 (d, J= 8.3 Hz, 1H), 7.54 (s, 1H), 6.95 (s, 1H), 6.87 (s, 2H), 6.77 (s, 1H), 4.56-4.42 (m, 2H), 4.38-4.28 (m, 1H), 1.43 (d, 7= 15.1 Hz, 7H), 1.24 (s, 3H) 271 Η ₂ Ν V/ ο ΗΝ-/ Νρ 334.2 1.66/1 6 8.85 (s, 1H), 8.41-8.39 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.98-7.96 (m, 1H), 7.78-7.77 (d, 7= 2.4 Hz, 1H ), 6.84-6.83 (d, J= 2.4 Hz, 1H), 4.87-4.86 (m, 2H), 4.21 (t, J= 8.3 Hz, 4H), 3.87-3.86 (t, J= 5.5 Hz, 2H) , 2.51(s, 2H). 272 0. Η ₂ Ν p-CH3 λ=( ^CH z Ο ΗΝ—Ζ Np 364.3 0.94/Β Ή NMR (300 MHz, Methanol^) δ 8.74-8.71 (d, J= 9.0 Hz, 1H), 8.35-8.32 (d, J= 8.2 Hz, 1H), 8.01-8.00 (m, 1H), 7.96-7.93 (m, 1H), 7.77-7.76 (m, 1H), 6.83-6.82 (d, 7=2.3 Hz, 1H), 4.74-4.70 (m, 2H), 4.03-3.90 (m, 2H), 3.43-3.36 (m, 2H), 2.08 (s, 2H), 1.75 (s, 1H), 1.16-1.10 (m, 3H) 273 Η ₂ Ν f 0 \u003d - ¹ ζ rn \u003d ρ ΗΝ-Ζ ^Ν Ρ 396.3 1.87/M δ 8.44 (s, 1H), 8.24 (d,7= 8.2 Hz, 1H), 7.91 (s, 1H), 7.71 (s, 2H), 6.76 (d, 7=2.0 Hz, 1H), 4.64-4.46 ( m, 3H), 1.48-1.37 (m, 9H)

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274 ,sn ₃ ιί^τ ^Ν ' L7 ⁿ Μ 362.2 0.71/N Ή NMR (300 MHz, Methanol A) δ 8.96 (s, 1H), 8.36-8.33 (d, J= 8.2 Hz, 1H), 8.04 (d,7= 1.5 Hz, 1H), 7.99-7.96 (m, 1H) , 7.78-7.77 (d, 7=2.3 Hz, 1H), 6.85-6.84 (d, 7= 2.4 Hz, 1H), 5.00-4.96 (m, 2H), 4.21-4.19 (m, 1H), 3.86-3.82 (m, 1H), 3.45-3.37 (m, 2H), 3.23-3.16 (m, 1H), 2.46-2.37 (m, 1H), 2.24-2.06 (m, 2H), 1.98-1.92 (m, 1H) , 1.42-1.38 (t, 7= 7.2 Hz, 3H). 275 CO Τ Ο C9 Ο ¹ vp ΙΖ^ % 'ζ 336.3 0.53/0 Ή NMR (300 MHz, Methanol^) δ 8.89 (s, 1H), 8.36-8.33 (d,7= 8.1 Hz, 1H), 8.03 (s, 1H), 7.98-7.95 (m, 1H), 7.78-7.77 (d, 7= 2.4 Hz, 1H), 6.84-6.83 (d, 7= 2.4 Hz, 1H), 4.91-4.70 (m, 2H), 3.783.75 (t, 7= 5.8 Hz, 2H), 3.603. 51 (m, 1H), 1.41-1.38 (d,7 = 6.5 Hz, 6H) 276 sn ₃ ⁿ u Γ^νΑ ⁰ V / ^Ν ο ΗΝ-/ ν'^ 405.3 1.17/S Ή NMR (400 MHz, DMSO7 ₆ ) δ 13.35 - 12.88 (m, 1H), 8.50 (s, 1H), 8.07 (d, 7=8.1 Hz, 1H), 7.87 (s, 1H), 7.79 7.63 (m, 2H), 6.89 (s, 2H), 6.75 (d, 7=2.1 Hz, 1H), 4.57 (t, 7= 6.2 Hz, 2H), 3.43 (m, 4H), 2.88 (t, 7= 6.2 Hz, 2H), 2.45 (m, 4H), 1.98 (s, 3H) 277 νη ₂ 1 <-ΝΗ A ' ^SNz ΛΑ' ^Η 1 Μ 308.3 0.70/Β Ή NMR (300 MHz, Methanol^) δ 8.46 (s, 1), 8.27-8.24 (d, 7= 8.2 Hz, 1H), 7.92 (s, 1H), 7.70 (s, 2H), 6.77-6.76 (d , 7= 2.2 Hz, 1H), 4.62-4.58 (t, 7=6.0 Hz, 2H), 3.22-3.18 (t, 7=6.1 Hz, 2H), 2.44 (s, 3H) 278 νη ₂ ? J%nx η ijT ^{Ν ng} O Μ 334.2 1.00/B δ 8.87(s, 1H), 8.40-8.38 (d, 7 = 8.3 Hz, 1H), 8.04 (s, 1H), 7.97-7.96 (m, 1H), 7.78 (s, 1H), 6.84-6.83 (d , 7= 2.4 Hz, 1H), 5.05-5.01 (m, 1H), 4.874.75 (m, 1H), 4.20-4.18 (m, 1H), 3.48-3.37 (m, 2H), 2.42 -2.38(m , 1H), 2.19-2.06 (m, 2H), 1.94-1.86 (m, 1H)

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279 τ' o J ΞΕ Z Z'z Va T ^z IZ z 322.1 0.64/N Ή NMR (300 MHz, Methanol^) δ 8.89 (s, 1H), 8.38-8.35 (d,7= 8.4 Hz, 1H), 8.04 (s, 1H), 7.98-7.95 (d,7= 8.4 Hz, 1H ), 7.77-7.76 (m, 1H), 6.84-6.83 (d, 7= 2.4 Hz, 1H), 4.99-4.90 (m, 2H), 3.763.72 (t, 7= 5.7 Hz, 2H), 3.253. 17 (q, 7= 7.2 Hz, 2H), 1.39-1.34 (t, 7= 7.3 Hz, ZN) 280 H h ₂ nn U x/^n' ^h xx n0J 348.3 1.06/A Ή NMR (300 MHz, Methanol-6A) δ 8.88 (s, 1H), 8.35-8.32 (d,7= 8.3 Hz, 1H), 8.01-7.98 (m, 1H), 7.96-7.92 (m, 1H), 7.77-7.76 (d,7=2.4Hz, 1H), 6.84-6.83 (d,7=2.4Hz, 1H), 4.87 (s, 2H), 3.933.83 (m, 1H), 3.66-3.62 (t, 7 = 5.6 Hz, 2H), 2.37-2.15 (m, 4H), 1.96-1.84 (m, 2H) 281 nh ₂ 1 CH ₃ JlAXT ⁿ ^AT^ _0H H ij ^N 323.2 1.22/Β 6 8.80 (s, 1H), 8.35-8.33 (d,7 = 8.3 Hz, 1H), 8.04-8.03 (m, 1H), 7.95-7.93 (m, 1H), 7.777.76 (d, 7=2.3 Hz , 1H), 6.83-6.82 (d, 7= 2.4 Hz, 1H), 4.99-4.88 (m, 1H), 3.62-3.57 (m, 1H), 3.35-3.33 (m, 1H), 2.36-2.34 (m , 1H), 2.20-2.10 (m, 1H), 1.72-1.70 (d,7=6.8 Hz, ZN) 282 nh ₂ H i) ^N ° ^H 309.2 1.19/Β δ 8.86 (s, 1H), 8.34-8.32 (d,7 = 8.3Hz, 1H), 8.12 (s, 1H), 8.02-7.94 (m, 1H), 7.79-7.78 (d, 7= 2.4Hz, 1H ), 6.85-6.84 (d, 7= 2.4 Hz, 1H), 4.57-4.57 (m, 1H), 4.43-4.31 (m, 2H), 1.39-1.38 (d, J = 5.8 Hz, ZN) 283 nh ₂ XH ₃ C YYY _n ALch ₃ ⁿ GT ^{N he} N^zY Μ 323.2 1.25/Β Ή NMR (300 MHz, Methanol^) δ 8.84 (s, 1H), 8.34-8.32 (d, 7= 8.7 Hz, 1H), 8.02 (s, 1H), 7.96-7.93 (m, 1H), 7.79-7.78 (d, 7= 2.4Hz, 1H), 6.85-6.84 (d,7= 1.8Hz, 1H), 4.48 (s, 2H), 1.30 (s, 6H) 284 νη ₂ 1 SNz ^η ί7 ^Ν Μ 323.2 2.03/Η δ 8.73(s, 1H), 8.29-8.29 (d,7 = 8.3 Hz, 1H), 7.98-7.97 (m, 1H), 7.93-7.90 (m, 1H), 7.777.76 (d, 7=2.4 Hz , 1H), 6.83-6.82 (d, 7= 2.3 Hz, 1H), 4.62-4.59 (m, 2H), 3.79-3.71 (m, 1H), 2.26-2.20 (m, 1H), 2.19-2.05 (m , 1H), 1.26-1.24 (d, 7=6.2 Hz, ZN) 285 νη ₂ 1 n ₃ with _ν Α<=α V ^ch 3 ϊ L ΛΑ aJU <γ 337.2 2.19/Η δ 8.75 (s, 1H), 8.32-8.30 (d, 7 = 8.3 Hz, 1H), 8.00 (s, 1H), 7.94-7.92 (m, 1H), 7.77-7.76 (d, 7= 2.4 Hz, 1H ), 6.83-6.82 (d, 7= 2.4 Hz, 1H), 4.65-4.61 (m, 2H), 2.24-2.20 (m, 2H), 1.31 (s, 6H)

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Example 286.

stage 1

stage 1

Step 1. Obtaining ethyl (2Z)-3-(4-bromo-2-nitrophenyl)-2-cyanopron-2-enoate.

To a 100 ml round bottom flask was added 4-bromo-2-nitrobenzaldehyde (8 g, 34.8 mmol, 1 eq.), H ₂ O (40 ml), ethyl 2-cyanoacetate (4.33 g, 38.2 mmol , 1.1 eq.), morpholine (0.30 g, 3.4 mmol, 0.1 eq.). The resulting solution was stirred at room temperature for 1 h. The resulting solution was diluted with 50 ml H2O. The resulting solution was extracted with 2x200 ml of ethyl acetate. The organic layer was washed with 2x200 ml of brine. The resulting solution was dried over anhydrous sodium sulfate and concentrated. This resulted in 11 g (97.3%) of ethyl (2Z)-3-(4-bromo-2-nitrophenyl)-2-cyanoprop-2-enoate as a yellow solid.

Stage 2. Obtaining 4-(4-bromo-2-nitrophenyl)-1H-pyrrole-3-carbonitrile.

Ethyl (2Z)-3-(4-bromo-2-nitrophenyl)-2-cyanoprop-2-enoate (12 g, 36.9 mmol, 1 eq.), EtOH (100 ml) was added to a 250 ml round bottom flask. EtONa in EtOH (16.7 ml, 44.7 mmol, 1.2 eq.) was then added dropwise with stirring at 5° C. for 30 minutes. To this reaction mixture was added dropwise a solution of TosMIC (8.65 g, 44.3 mmol, 1.2 eq.) in DCM (50 ml) with stirring at 5° C. for 20 minutes. The resulting solution was stirred for 2 hours at 25°C. The resulting solution was diluted with 500 ml H2O. The pH of the solution was adjusted to 8 with concentrated HCl. The resulting solution was extracted with 3x500 ml DCM. The resulting mixture was washed with 2x500 ml of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was applied to a silica gel column using ethyl acetate/petroleum ether (1:3). This resulted in 6.8 g (63.1%) of 4-(4-bromo-2-nitrophenyl)-1H-pyrrole-3-carbonitrile as a yellow solid. LC-MS (ES, m/z): [M+H]+=291.9. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.41 (d, J=1.9 Hz, 1H), 8.15 (dd, J=8.3, 1.9 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H) , 7.74 (d, J=11.9 Hz, 1H), 6.19 (d, J=11.7 Hz, 1H).

Step 3. Preparation of tert-butyl N-[2-[3-(4-bromo-2-nitrophenyl)-4-cyano-1H-pyrrol-1yl]ethyl]carbamate.

4-(4-Bromo-2-nitrophenyl)-1H-pyrrole-3-carbonitrile (1.8 g, 6.2 mmol, 1 eq.), DMF (15 ml), Cs ₂ CO ₃ (6.02 g, 18.5 mmol, 3 eq.), tert-butyl N-(2bromoethyl)carbamate (2.07 g, 9.2 mmol, 1.5 eq.). The resulting solution was stirred for 3 hours at 80°C. The resulting solution was diluted with 100 ml H ₂ O. The resulting solution was extracted with 3x100 ml ethyl acetate. The resulting mixture was washed with 3x100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 2.1 g (78.3%) of tert-butyl N-[2-[3-(4-6pom-2nitrophenyl)-4-cyano-1H-nurrol-1-yl]ethyl]carbamate as yellow oil. LC-MS: (ES, m/z): [M+H] ⁺ =435.1. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 8.12 (d, J=2.0 Hz, 1H), 7.86 (dd, J=8.3, 2.0 Hz, 1H), 7.527.44 (m, 2H), 6.98- 6.93 (m, 1H), 4.06 (t, J=6.1 Hz, 2H), 3.39 (t, J=5.9 Hz, 2H), 1.40 (s, 9H).

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Step 4. Preparation of tert-butyl N-(2-[4-amino-7-bromo-2H-pyrrolo[3,4-c]quinolin-2yl]ethyl)carbamate.

tert-Butyl N-[2-[3-(4-bromo-2-nitrophenyl)-4cyano-1H-pyrrol-1-yl]ethyl]carbamate (2.1 g, 4.8 mmol, 1 eq.), HOAc (20 ml). After that, Fe (1.35 g, 24.3 mmol, 5 eq.) was added in portions at 50°C. The resulting solution was stirred for 2 hours at 50°C. The resulting solution was diluted with 100 ml of MeOH. Solids were filtered off. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using dichloromethane/methanol (15:1). This resulted in 1.8 g (92.1%) of tert-butyl N-(2-[4-amino-7-bromo-2Hpyrrolo[3,4-c]quinolin-2-yl]ethyl)carbamate as yellow solid. LC-MS (ES, m/z): [M+H]+=405.1 ¹ H NMR (300 MHz, DMSO-φ) δ 7.76 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 7.60 (s, 1H), 7.46 (d, J=1.7 Hz, 1H), 7.25-7.17 (m, 1H), 7.17-6.91 (m, 3H), 4.21 (t, J=5.6 Hz, 2H), 3.36 (q, J=5.7 Hz, 2H), 1.35 (s, 9H).

Step 5. tert-butyl N-(2-[4-amino-7-[1-(oxan-2-yl)-1 H-pyrazol-5-yl]-2H-pyrrolo[3,4-c]quinoline2 -yl]ethyl)carbamate.

Into a 50 ml round bottom flask, purged and maintained under an inert nitrogen atmosphere, was placed tert-butyl N-(2-[4-amino-7-bromo-2H-pyrrolo[3,4-c]quinolin-2-yl]ethyl )carbamate (1.8 g, 4.441 mmol, 1 eq.), 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ul )-1H-pyrazole (1.85 g, 6.662 mmol, 1.5 eq.), Cs ₂ CO ₃ (4.34 g, 13.324 mmol, 3 eq.), dioxane (20 ml), Pd(dppf)Cl _2. CH ₂ Cl ₂ (0.73 g, 0.888 mmol, 0.2 eq.), H2O (0.5 ml). The resulting solution was stirred for 16 hours at 90°C. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using dichloromethane/methanol (12:1). This resulted in 1.8 g (85%) tert-butyl N-(2-[4-amino-7-[1-(oxan2-yl)-1H-pyrazol-5-yl]-2H-pyrrolo[3 ,4-c]quinolin-2-yl]ethyl)carbamate as a yellow solid. LC-MS (ES, m/z): [M+H]+=477.2.

Step 6 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)-2H-pyrrolo[3,4-c]quinoline-4-amine

tert-Butyl N-(2-[4-amino-7-[1-(oxan-2-yl)-1Hpyrazol-5-yl]-2H-pyrrolo[3,4-c] quinolin-2-yl]ethyl)carbamate (1.6 g, 3.357 mmol, 1 eq.), HCl (gas) in 1,4-dioxane (20 ml). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated. This resulted in 1.4 g of 2-(2-aminoethyl)-7-(1H-pyrazol-5-yl)2H-pyrrolo[3,4-c]quinoline-4-amine as a yellow solid. LC-MS-PH-BMS-L15-001-6: (ES, m/z): [M+H]+=293.1. 1H NMR (400 MHz, Methanol^) δ 8.13-8.04 (m, 2H), 7.92-7.83 (m, 2H), 7.83-7.86 (m, 1H), 7.80-7.75 (d, J=2.3 Hz, 1H) , 6.80 (d, J=2.3 Hz, 1H), 4.65 (t, J=6.3 Hz, 2H), 3.58 (t, J=6.2 Hz, 2H).

Step 7: Preparation of N-[2-[4-amino-7-(1H-pyrazol-5-yl)-2H-pyrrolo[3,4-c]quinolin-2yl]ethyl]pyridine-2-carboxamide.

2-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)-2Hpyrrolo[3,4-c]quinoline-4-amine (150 mg, 0.282 mmol, 1 eq. , 55%), DCM (5 ml), HATU (161 mg, 0.423 mmol, 1.50 eq.), DIEA (129 mg, 0.998 mmol, 3.54 eq.), pyridine-2-carboxylic acid (35 mg 0.284 mmol, 1.01 eq.). The resulting solution was stirred for 2 hours at room temperature. The resulting mixture was concentrated. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18, 30x150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min; gradient: 15 to 27% B in 7.5 minutes; 254/210 nm; RT: 6.87 min. This resulted in 14.9 mg (13.13%) of N-[2-[4-amino-7-(1H-pyrazol-5-ul)2H-pyrrolo[3,4-c]quinolin-2-yl ]ethyl]pyridine-2-carboxamide as a light yellow solid. LC-MS: (ES, m/z): [M+H]+=398.3 1H NMR (400 MHz, DMSO-d6) δ 12.78-12.74 (m, 1H), 9.25 (s, 1H), 9.09 (t , J=6.0 Hz, 1H), 8.57-8.65 (m, 2H), 8.13 (d, J=1.9 Hz, 1H), 8.05-7.94 (m, 5H), 7.74-7.78 (m, 2H), 7.61- 7.74 (m, 1H), 6.76 (d, J=2.3 Hz, 1H), 4.50 (t, J=6.0 Hz, 2H), 3.78-3.96 (m, 2H).

Examples 287 and 288.

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Step 1 Ethyl 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3c]quinolin-2-yl )butanoate.

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (100 mg, 0.299 mmol) and carbonate cesium (292 mg, 0.897 mmol) in DMF (997 μl) was added ethyl 3-bromobutanoate (87 mg, 0.449 mmol). The suspension was stirred at 70° C. for 3 hours. Additional ethyl 3-bromobutanoate (87 mg, 0.449 mmol) was added. The reaction mixture was stirred at 70°C for 2 h and then cooled to room temperature. The reaction mixture was diluted with H ₂ O (20 ml) and was extracted with EtOAc (3x20 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOHCH ₂ Cl ₂ ) to give ethyl 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H -pyrazol-5-yl)-2Hpyrazolo[4,3-c]quinolin-2-yl)butanoate (85.8 mg, 0.191 mmol, 64.0% yield) as a white solid.

LC-MS m/z 449 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 8.56 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.59 (dd, J=5.1, 1.6 Hz, 2H), 7.31 (d, J =8.2 Hz, 1H), 6.99 (s, 2H), 6.50 (d, J=1.7 Hz, 1H), 5.29 (br d, J=9.7 Hz, 1H), 5.125.02 (m, 1H), 4.09- 3.95 (m, 3H), 3.58 (br t, J=9.4 Hz, 1H), 3.15-3.06 (m, 1H), 3.05-2.97 (m, 1H), 2.47-2.37 (m, 1H), 1.99-1.92 (m, 1H), 1.83-1.74 (m, 1H), 1.63 (d, J=6.7 Hz, 3H), 1.55 (br t, J=8.6 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H ).

Step 2 3-(4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)butan-1-ol.

To a suspension of ethyl 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3s]quinolin-2-yl) butanoate (85 mg, 0.190 mmol) in THF (1895 μl) was added dropwise lithium borohydride (2 M solution in THF) (284 μl, 0.569 mmol). The reaction mixture was stirred at room temperature for 2 hours. Additional lithium borohydride (2 M solution in THF) (284 μl, 0.569 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1.25 h before methanol (46.1 µl, 1.137 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (4x20 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was dissolved in MeOH (630 μl) and 4 M hydrogen chloride in dioxane (47.4 μl, 0.190 mmol) was added. The reaction mixture was diluted with MeOH (1.5 ml) and CH2Cl2 (1.5 ml) (to give a clear solution) and carbonate on silica (SiliBond carbonate, Silicycle, 0.51 mmol/g) (1.5 g, 0.765 mmol). The suspension was stirred at room temperature for 1 h. The mixture was filtered and washed with 50% MeOH-CH ₂ Cl ₂ (3x6 ml). Celite was added to the filtrate (enough to fill a 5 g cartridge). The mixture was concentrated in vacuo. This product was dry-loaded and purified by flash chromatography (RediSep Gold with 12 g silica gel with 5 g solid-load cartridge; linear gradient 0-70% MeOH-CH ₂ Cl ₂ ) to give 3-(4-amino-7-( 1H-pyrazol-3-yl)-2H-pyrazolo[4,3c]quinolin-2-yl)butan-1-ol (38 mg, 55%). LCMS m/z 323.6 [M+H] ⁺ .

The racemic compound was then purified with preparative chiral SFC using the following conditions to give the compounds of Examples 287 and 288 as individual undefined isomers: instrument: Berger SFC MGII: column: ChiralCEL YMC SB, 30x250 mm, 5 µm; mobile phase: 85% CO ₂ /15% MeOH with 0.1% NH4OH; flow rate: 85 ml/min; detector wavelength: 220 nm. Example 287 (first eluting isomer). Example 288 (second eluting isomer).

Analytical Chiral SFC Conditions: Instrument: Agilent analytical SFC; column: YMC SB, 4.6x250 mm, 5 microns; mobile phase: 85% CO ₂ /15% IPA with 0.1% NH4OH; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 287 (first eluting isomer), retention time: 30.9 min. Example 288 (second eluting isomer), retention time: 33.4 min.

Example 287: LC-MS m/z 323 [M+H]+; ¹ H NMR (400 MHz, DMSO-d6) δ 13.47-12.74 (m, 1H), 8.61 (br s, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.00-6.94 (m, 5H), 6.77 (br s, 1H), 4.88-4.77 (m, 1H), 4.61 (br t, J=4.7 Hz, 1H), 3.43-3.35 (m, 1H), 3.26-3.18 (m, 1H), 2.20- 2.10 (m, 1H), 2.04-1.94 (m, 1H), 1.58 (br d, J=6.6 Hz, 3H).

Example 288: LC-MS m/z 323 [M+H]+; 1Н NMR (400 MHz, DMSO-d6) δ 13.41-12.85 (m, 1H), 8.59 (br s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.99-6.91 (m, 5H), 6.76 (br s, 1H), 4.87-4.77 (m, 1H), 4.61 (t, J=4.9 Hz, 1H), 3.423.34 (m, 1H), 3.26-3.18 (m, 1H), 2.20-2.10 ( m, 1H), 2.04-1.93 (m, 1H), 1.58 (d, J=6.6 Hz, 3H).

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Example 289 Preparation of (2R)-3-[4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl]-2methoxypropan-1-ol, HCl.

Step 1. 2-((R)-2-methoxy-3-(trityloxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5yl)-2H-pyrazolo[ 4,3-c]quinoline-4-amine.

To a solution of (R)-2-methoxy-3-(trityloxy)propan-1-ol (156 mg, 0.449 mmol) in CH ₂ Cl ₂ (997 μl) at a temperature of 0 ° C was added triethylamine (125 μl, 0.897 mmol) , then methanesulfonyl chloride (34.7 µl, 0.449 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H2O (2 ml) and extracted with CH ₂ Cl ₂ (2x2 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo.

The crude product was dissolved in DMF (997 μl) and added to a mixture of 7-(1-(tetrahydro-2Hpyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-4 -amine (100 mg, 0.299 mmol) and cesium carbonate (292 mg, 0.897 mmol). The suspension was stirred at room temperature for 2 hours, then at 40°C for 3 hours and then at room temperature overnight. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (2x30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (RediSep Gold with 24 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give 2-((R)-2-methoxy-3-(trityloxy)propyl)-7- (1(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine (80 mg, 40%) as white solid . The product corresponded to the second of the two observed regioisomeric peaks eluted from the column. LC-MS m/z 665 [M+H]+; 1Н NMR (400 MHz, DMSO-d ₆ ) δ 8.48-8.44 (m, 1H), 8.13-8.08 (m, 1H), 7.61-7.57 (m, 2H), 7.45-7.40 (m, 6H), 7.36- 7.29 (m, 7H), 7.28-7.22 (m, 3H), 7.01 (s, 2H), 6.52-6.47 (m, 1H), 5.34-5.28 (m, 1H), 4.68-4.53 (m, 2H), 4.09-4.00 (m, 1H), 3.92-3.84 (m, 1H), 3.63-3.51 (m, 1H), 3.22-3.19 (m, 3H), 3.25-3.15 (m, 1H), 3.05-2.97 (m , 1H), 2.44-2.36 (m, 1H), 1.98-1.91 (m, 1H), 1.841.76 (m, 1H), 1.63-1.48 (m, 3H).

Step 2. (R)-3-(4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)--2-methoxypropan1-ol, HCl.

To a solution of 2-((R)-2-methoxy-3-(trityloxy)propyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol5-yl)-2H-pyrazolo[4 ,3-c]quinoline-4-amine (80 mg, 0.120 mmol) in MeOH (401 μl) was added 4 M hydrochloric acid in dioxane (90 μl, 0.361 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was added to Et ₂ O (6 ml) and the resulting solids were collected by vacuum filtration and washed with Et ₂ O (3x2 ml). The solids were dissolved in 1:1 MeCN-H ₂ O (2 ml), filtered, frozen at -78°C and lyophilized to give (R)-3-(4-amino-7-(1H-pyrazole-3- yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methoxypropan-1-ol, HCl (34 mg, 75% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 9.819.66 (m, 1H), 8.97 (s, 1H), 8.68-8.53 (m, 1H), 8.20 (d, J =8.2 Hz, 1H), 8.12 (d, J=1.1 Hz, 1H), 7.92 (dd, J=8.2, 1.5 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 6.82 (d, J =2.3Hz, 1H), 4.67 (dd, J=14.1, 3.5Hz, 1H), 4.52 (dd, J=14.1, 7.7Hz, 1H), 3.71 (td, J=8.1, 5.0Hz, 1H), 3.53 (d, J=5.1 Hz, 2H), 3.26 (s, 3H). Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). m/z 339.2 [M+H]+; RT: 0.52 min.

Compounds of examples 290-302 were prepared according to synthetic procedures similar to those described in examples 150 and 151 from the corresponding starting compounds. Ana conditions

- 136 042018 lytic LC/MS: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). Compounds of examples 300 and 299 were obtained as individual undefined isomers by purifying the racemic compound with chiral SFC under the following conditions: instrument: Waters 100 Prep SFC; column: Chiral IC, 21x250 mm, 5 µm; mobile phase: 60% CO ₂ /40% MeOH with 0.1% DEA; flow rate: 60 ml/min; detector wavelength: 220 nm. Compound of example 300 (first eluting isomer) RT: 7.50 min. Example 299 compound (second eluting isomer). Retention time: 9.91 min. Analytical Chiral Conditions SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral AD, 4.6x100 mm, 5 µm; mobile phase: 85% CO ₂ /15% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Compound of example 300 (first eluting isomer), retention time: 5.3 min. Compound of Example 299 (second eluting isomer), retention time: 6.8 min.

Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 290 ^H2 V H L \ NN h SI N. >NY ' O N=/ HN^ 336.2 1.0 5 8.43 (s, 1H), 8.09 (d, 7=8.2 Hz, 1H), 8.07 - 8.04 (m, 1H), 7.87 (s, 1H), 7.77 - 7.66 (m, 1H), 7.63 (br d, 7=6.4Hz, 1H), 7.07 - 6.89 (m, 2H), 6.75 (d, 7=1.8Hz, 1H), 4.45 (t, 7=6.0Hz, 2H), 3.65 -3.59 (m, 2H), 1.80(s, 3H) 291 ~ N CN Ν >Ν ΪΎ ° Ο ΗΝ^ 387.2 1.09 5 8.43 (s, 1H), 8.35 (brs, 1H), 8.10 (d, 7=8.2 Hz, 1H), 7.87 (brs, 1H), 7.78 - 7.59 (m, 2H), 7.06 - 6.90 (m, 2H ), 6.76 (d, 7=1.4 Hz, 1H), 4.53 -4.47 (m, 2H), 3.68 - 3.64 (m, 2H), 1.55-1.51 (m, 2H), 1.421.38 (m, 2H) 292 Ο Vch ₃ νη ₂ ην OH Ν^Α^ ην' Ύ 366.1 0.66 5 13.33 - 13.04 (m, 2H), 9.76 - 9.58 (m, 1H), 8.98-8.88 (m, 1H), 8.86 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.14-8.06 (m, 1H), 7.97 (d, 7=8.5 Hz, 1H), 7.92 (br d, 7=7.7 Hz, 1H), 7.84 (brs, 1H), 6.82 (d, 7=1.9 Hz, 1H), 5.17-5.03 (m, 1H), 4.66 (dd, 7=13.8, 4.7 Hz, 1H), 4.45 (dd, 7=13.6, 8.1 Hz, 1H), 4.30-4.21 (m, 1H), 3.503.44 ( m, 2H), 1.78 (s, 3H)

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293 t ζ AT /Aga - ¹ c V GA ι °C? '—A o 445.1 1.29 δ 13.49-13.07 (m, IH), 9.59 (br s, IH), 9.06 (br s, IH), 8.86 (s, IH), 8.64 (d, 7=2.5 Hz, IH), 8.58 (s, IH ), 8.17 (dd, 7=8.7, 4.5 Hz, IH), 8.09 (brd,7=8.3 Hz, 2H), 7.987.91 (m, 2H), 7.90 - 7.83 (m, IH), 6.80 (brs, IH), 4.89 (s, 2H), 1.48 (s, 6H) 294 o /^\ s _s H ₃ C / \,_/ ^Η ₂ N ^ό \^ΝΗ Ν—' H XX ^N /J 431.2 1.30 δ 9.06 (br d, 7=7.6 Hz, IH), 8.66 (d, 7=1.8 Hz, IH), 8.47 (s, IH), 8.08 (d, 7=8.2 Hz, IH), 8.04 (dd, 7 =8.5, 4.3 Hz, IH), 7.93 - 7.82 (m, 2H), 7.71 (br s, IH), 7.66 (br d, 7=7.3 Hz, IH), 6.76 (s, IH), 4.74 4.54 (m , 3H), 1.21 (br d, 7=5.8 Hz, 3H) 295 F O /=( s m H ₃ C / / ^Η ₂ Ν ^J \ ΝΗ Ν—' kA ^η Xw ^N kX 431.18 1.29 δ 9.22 (br d, 7=7.7 Hz, IH), 8.79 - 8.66 (m, IH), 8.48 (s, IH), 8.08 (d, 7=8.2 Hz, IH), 7.87 (s, IH), 7.79 - 7.69 (m, 2H), 7.66 (br d, 7=8.2 Hz, IH), 7.57 - 7.42 (m, IH), 6.77 (d, 7=1.9 Hz, IH), 4.73 -4.50 (m, 3H) , 1.22 (brd, 7=5.7Hz, 3H) 296 AW _ Η D—y nW-ν. Ν > Ν _n G X ° CH ₃ ^NzC o O hn- / n'A 380.05 1.01 δ 8.45 (s, IH), 8.07 (d, 7=8.1 Hz, IH), 8.02 (d, 7=8.3 Hz, IH), 7.89 (s, IH), 7.73 (br s, IH), 7.64 (brd ,7=7.9 Hz, IH), 6.77 (d, 7=1.8 Hz, IH), 4.57-4.35 (m, 3H), 3.28 (s, 2H), 1.92 (s, 3H), 1.12 (d, 7= 6.6Hz, 3H) 297 ^Η 2 ^Ν / k n 9 ^N z 2-G NXN _x J Ν > _n G AND VKh ^{n s} 0 O ην-Α 364.3 1.07 δ 8.41 (s, IH), 8.08 (d, 7=8.1 Hz, IH), 7.90 - 7.82 (m, 2H), 7.72 (brs, IH), 7.66-7.61 (m, IH), 6.77 (d, 7 =1.9 Hz, IH), 4.49 -4.34 (m, 2H), 4.31 -4.21 (m, IH), 2.05 (q, 7=7.5 Hz, 2H), 1.10 (d, 7=6.7 Hz, 3H), 0.94 (t, 7=7.6Hz, 3H) 298 θΧ _N ^z/ Vn ch ₃ о hnA nA 394.3 1.12 δ 8.48 (s, IH), 8.09 (brd, 7=7.9 Hz, IH), 7.97 - 7.85 (m, 2H), 7.72 (brs, IH), 7.66 (br d, 7=7.6 Hz, IH), 6.77 (br d, 7=1.5 Hz, IH), 4.50 (br d, 7=5.2 Hz, 2H), 4.44 - 4.37 (m, IH), 3.84 -3.72 (m, 2H), 3.47 -3.33 (m, 2H ), 1.17 - 1.07 (m, 6H)

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299 ΗτΝ _n Ν XN,..... Chk ^Ν ~ ^Ν H C ^1G χ... ^H 3 ^C O HN- - _N .. enantiomer 1 350.18 0.98 5 8.42 (s, 1H), 8.09 (d, 7=7.9 Hz, 1H), 7.94 (d, 7=7.6 Hz, 1H), 7.88 (d, 7=1.2 Hz, 1H), 7.72 (brd,7= 1.5 Hz, 1H), 7.63 (br d, 7=7.3 Hz, 1H), 6.76 (d, 7=2.1 Hz, 1H), 4.41 (d, 7=6.1 Hz, 2H), 4.34 - 4.20 (m, 1H ), 1.81 (s, 3H), 1.10 (d, 7=6.7 Hz, 3H) 300 H?N ., \ χ, H XA 'isr X-A ,., cn ₃ ΗΝ-χ \\ enantiomer 2 350.19 0.99 5 8.42 (s, 1H), 8.09 (d, 7=7.9 Hz, 1H), 7.94 (d, 7=7.6 Hz, 1H), 7.88 (d, 7=1.2 Hz, 1H), 7.72 (brd,7= 1.5 Hz, 1H), 7.63 (br d, 7=7.3 Hz, 1H), 6.76 (d, 7=2.1 Hz, 1H), 4.41 (d, 7=6.1 Hz, 2H), 4.34 - 4.20 (m, 1H ), 1.81 (s, 3H), 1.10 (d, 7=6.7 Hz, 3H) 301 ^ΗζΝ \ n o N'VN.II ^N '>NJF ^{C 3} X/ ⁿ z ° ⁰ O HN-Z 385.9 1.04 5 8.81 (s, 1H), 8.20 (d, 7=8.2 Hz, 1H), 8.03 (brs, 1H), 7.88 (brd,7=7.0 Hz, 1H), 7.847.68 (m, 1H), 6.82 ( d, 7=2.1 Hz, 1H), 4.50 (dd, 7=13.6, 5.0 Hz, 1H), 4.38 (dd, 7=13.7, 7.9 Hz, 1H), 3.99 - 3.85 (m, 1H), 3.77 (brs , 1H), 1.22 (d, 7=6.4 Hz, 3H) 302 ^h ₂ n X 386.2 1.07 5 8.92 (s, 1H), 8.23 (brd, 7=8.5Hz, 1H), 8.08 (brs, 1H), 7.93 (brd,7=6.7Hz, 1H), 7.83 (brd,7=1.5Hz, 1H) , 7.25 (brs, 1H), 6.83 (s, 1H), 4.82 (brd,7=6.4Hz, 2H), 1.59 (brd, 7=6.7Hz, 3H)

The compounds of examples 303-406 were prepared according to synthetic procedures similar to those described in example 207 and example 208, example 209, example 210 or example 210 from the appropriate starting compounds, alkyl halide, mesylate, tosylate, epoxide or alcohol, which, in in some cases may contain suitable protecting groups. The temperature of the alkylation reactions ranged from room temperature to 90° C. and, in some cases, additional equivalents of the alkylating agent were added. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Compounds of the following examples were obtained as individual undefined isomers by purifying the racemic compound with chiral SFC under the following conditions: Compounds of examples 315 and 316: instrument: Waters 100 Prep SFC; column: Chiral AD, 3x250 mm, 5 µm; mobile phase: 75% CO2/25% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 315 (first eluting isomer), retention time: 10.61 min. Example 316 (second eluting isomer), retention time: 14.97 minutes. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiralpak AD, 4.6x100 mm, 5 microns; mobile phase: 75% CO2/25% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 315 (first eluting isomer), retention time: 5.2 min. Example 316 (second eluting isomer), retention time: 7.0 min.

Examples 318 and 319: Apparatus: Waters 100 Prep SFC; column: Chiral AD, 30x250 mm, 5 µm; mobile phase: 65% CO ₂ /35% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 318 (first eluting isomer), retention time: 5.47 min. Example 319 (second eluting isomer), retention time: 11.53 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiralpak AD, 4.6x100 mm, 5 microns; mobile phase: 65% CO ₂ /35% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 318 (first eluting isomer), retention time: 2.6 min. Example 319 (second eluting isomer), retention time: 5.2 min.

Examples 324 and 325: Apparatus: Berger SFC MGII; column: CHIRALCEL AS SFC 30x250 mm ID, 5 µm; mobile phase: 78/18 CO ₂ /(MeOH with 0.5% DEA); flow rate: 65 ml/min; detector wavelength: 270 nm. Example 324 (first eluting isomer), retention time: 60 min. Connect

- 139 042018 Example 325 (second eluting isomer), retention time: 65 min. Analytical chiral SFC conditions: instrument: Agilent analytical SFC; column: AS 4.6x250 mm ID, 5 µm; mobile phase: 85/15 CO ₂ /(MeOH with 0.5% DEA); flow rate: 2 ml/min. Example 324 (first eluting isomer), retention time: 44.0 min. Example 325 (second eluting isomer), retention time: 48.4 min.

Examples 327 and 328: Apparatus: Berger SFC MGII; column: CHIRALCEL YMC SB SFC 30x250 mm ID, 5 µm; mobile phase: 78/18 CO ₂ /(MeOH with 0.5% DEA); flow rate: 85 ml/min; detector wavelength: 265 nm. Example 327 (first eluting isomer), retention time: 55 min. Example 328 (second eluting isomer), retention time: 61 min. Analytical chiral SFC conditions: instrument: Agilent analytical SFC; column: YMC SB, 4.6x250 mm ID, 5 µm; mobile phase: 80/20 CO ₂ /(MeOH with 0.5% DEA); flow rate: 2 ml/min. Example 327 (first eluting isomer), retention time: 22.3 min. Compound of Example 328 (second eluting isomer), retention time: 25.5 min.

Examples 337 and 338: Apparatus: Waters 100 Prep SFC; column: Chiral OJ, 30x250 mm, 5 µm; mobile phase: 90% CO ₂ /10% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 337 (first eluting isomer), retention time: 16.36 min. Example 338 (second eluting isomer), retention time: 26.8 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral OJ, 4.6x100 mm, 5 microns; mobile phase: 90% CO2/10% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 337 (first eluting isomer), retention time: 9.9 min. Example 338 (second eluting isomer), retention time: 14.3 min.

Examples 341 and 342: Apparatus: Waters 100 Prep SFC; column: Chiral AD, 30x250 mm. 5 µm; mobile phase: 65% CO ₂ /35% IPA-ACN 50-50 with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 341 (first eluting isomer), retention time: 17.91 min. Example 342 (second eluting isomer), retention time: 22.64 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral AD, 4.6x100 mm, 5 microns; mobile phase: 65% CO ₂ /35% IPA-ACN 50-50 with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Compound of example 341 (first eluting isomer), holding time: 7.2 min. Example 342 (second eluting isomer), retention time: 8.8 min.

Examples 344 and 345: Apparatus: Waters 100 Prep SFC; column: Chiral OD, 30x250 mm, 5 µm; mobile phase: 80% CO ₂ /20% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 344 (first eluting isomer), retention time: 23.91 min. Compound of Example 345 (second eluting isomer), retention time: 29.15 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral OD, 4.6x100 mm, 5 microns; mobile phase: 80% CO2/20% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 344 (first eluting isomer), retention time: 8.0 min. Example 345 (second eluting isomer), retention time: 9.8 min.

Examples 346 and 347: Apparatus: Waters 100 Prep SFC; column: Chiral AD, 30x250 mm. 5 µm; mobile phase: 85% CO ₂ /15% MeOH with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 346 (first eluting isomer), retention time: 21.99 min. Example 347 compound (isomer, second eluting isomer). Retention time: 26.03 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral AD, 4.6x100 mm, 5 microns; mobile phase: 85% CO ₂ /15% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 346 (first eluting isomer), retention time: 10.8 min. Example 347 (second eluting isomer), retention time: 12.9 min.

Examples 376 and 377: Apparatus: Waters 100 Prep SFC; column: Chiral IC, 21x250 mm, 5 µm; mobile phase: 75% CO ₂ /25% MeOH with 0.1% DEA; flow rate: 60 ml/min; detector wavelength: 220 nm. Compound of Example 376 (first eluting isomer), retention time: 26.43 min. Compound of Example 377 (second eluting isomer), retention time: 30.30 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral IC, 4.6x150 mm, 5 microns; mobile phase: 75% CO ₂ /25% MeOH with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 376 (first eluting isomer), retention time: 19.6 min. Example 377 compound (second eluting isomer). Retention time: 21.9 min.

Examples 378 and 379: Apparatus: Waters 100 Prep SFC; column: chiral OD, 30x250 mm. 5 µm; mobile phase: 65% CO ₂ /35% IPA with 0.1% DEA; flow rate: 100 ml/min; detector wavelength: 220 nm. Example 378 (first eluting isomer), retention time: 6.98 min. Compound of Example 379 (second eluting isomer), retention time: 10.17 min. Conditions for Analytical Chiral SFC: Instrument: Shimadzu Nexera UC SFC; column: Chiral OD, 4.6x100 mm, 5 microns; mobile phase: 65% CO ₂ /35% IPA with 0.1% DEA; flow rate: 2 ml/min; detector wavelength: 220 nm. Example 378 (first eluting isomer), retention time: 2.4 min. Example 379 (second eluting isomer), retention time: 3.0 min.

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Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 303 H ₂ N Χ^-χ Ν \=^ OCH ₃ Ο Ν=Ζ ΗΝ^ 323.2 1.00 5 8.48 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H), 7.71 (br s, 1H), 7.64 (brd,7=8.3 Hz, 1H), 7.17-7.00 (m, 2H), 6.76 (d, 7=1.7 Hz, 1H), 4.45 (brt, 7=6.9 Hz, 2H), 3.31 (brt, 7=6.0 Hz, 2H), 3.24 (s, 3H), 2.14 (quin, 7=6.5Hz, 2H) 304 Η ₂ Ν j--y Ο Ν=/ ΗΝ^ 348.2 0.88 5 9.01 (s, 1H), 8.21 (d, 7=8.3 Hz, 1H), 8.11 (brs, 1H), 7.94 (brd,7=7.7 Hz, 1H), 7.85 (br s, 1H), 6.82 (d , 7=1.9 Hz, 1H), 4.91 (brt, 7=5.9 Hz, 2H), 3.85 -3.79 (m, 2H), 2.05 - 1.83 (m, 4H); two CH protons are not visible, probably due to overlap with the suppressed water peak. 305 Η ₂ Ν Ν V^j CH ₃ 0 Ν=/ ΗΝ^ 307.2 1.18 5 8.71 -8.62 (br, 1H), 8.13 (d, 7=8.0 Hz, 1H), 7.97 (br s, 1H), 7.83 - 7.70 (m, 2H), 6.78 (s, 1H), 4.45 (brt, 7=6.9 Hz, 2H), 1.94 - 1.86 (m, 2H), 1.31 (sxt, 7=7.4 Hz, 2H), 0.92 (t, 7=7.4 Hz, ZN) 306 Η ₂ Ν Ν Lf] OH ⁴ ^-OCH3 Ν=/ ην^ 339.3 1.00 5 8.64 (s, 1H), 8.49 (d,7=8.9 Hz, 1H), 8.19 (brd, 7=2.4 Hz, 1H), 7.96 (brd,7=7.6 Hz, 1H), 7.90 - 7.83 (br, 1H), 6.87 (s, 1H), 4.86 - 4.73 (br, 2H), 4.15 (brs, 1H), 3.42 (br s, 2H), 3.32 (s, 3H) 307 η ₂ ν HO ° ^CH3 0 Ν=/^ ΗΝ^ 339.1 0.84 5 8.88 (s, 1H), 8.20 (d, 7=8.2 Hz, 1H), 8.06 (brd, 7=1.2 Hz, 1H), 7.91 (brd, 7=8.2 Hz, 1H), 7.81 (brs, 1H) , 6.82 (s, 1H), 4.54 (dd,7=13.7, 3.1 Hz, 1H), 4.37 (dd,7=13.7, 8.5 Hz, 1H), 4.09 (brs, 1H), 3.403.34 (m, 2H ), 3.31 (s, 3H) 308 n ₃ s, η ₂ ν '<^χ \ ^χ / he Ν^Τ I Ο Ν "' ΗΝ 3 323.2 1.00 5 8.87 (s, 1H), 8.19 (d, 7=8.0 Hz, 1H), 8.12-8.03 (m, 1H), 7.91 (brd,7=8.3 Hz, 1H), 7.87 - 7.79 (m, 1H), 6.82 (s, 1H), 4.96 -4.83 (m, 1H), 4.52 (dd, 7=13.6, 5.9 Hz, 1H), 4.30 (dd, 7=13.2, 8.0 Hz, 1H), 3.34 (brt, 7= 5.6 Hz, 2H), 2.302.20 (m, lH), 0.85 (d, 7=6.9 Hz, ZN)

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309 H ₂ N ^N . \=N OH O N=/ HN^ 339.2 0.74 5 8.93 (s, 1H), 8.19 (brd, 7=8.3 Hz, 1H), 8.10 (brs, 1H), 7.91 (brd,7=8.0 Hz, 1H), 7.87 -7.80 (m, 1H), 6.81 ( s, 1H), 4.66 (brt, 7=4.4Hz, 2H), 4.29 -3.97 (m, 4H), 3.92 (brt, 7=4.4Hz, 2H) 310 h ₂ n N ^N . OCH ₃ O Ν=Λ HN^ 353.2 0.93 5 8.92 - 8.88 (m, 1H), 8.19 (br d,7=8.1Hz, 1H), 8.10 (brs, 1H), 7.92 (brd,7=8.1Hz, 1H), 7.88 - 7.82 (m, 1H) , 6.82 (s, 1H), 4.65 (br d, 7=4.3 Hz, 2H), 3.91 (brs, 2H), 3.41 3.38 (m, 2H), 3.18-3.16 (m, 3H); two CH protons are not visible, probably due to overlap with the suppressed water peak. 311 nh ₂ 0jC ⁿ £j V hn' ] \ ) 335.2 0.92 5 8.38 (s, 1Н), 8.27 (d,7=8.5 Hz, 1Н), 8.03 (s, 1Н), 7.817.73 (m, 2Н), 7.34-7.15 (br, 2Н), 6.81 (d, 7 =1.9 Hz, 1H), 5.34-5.26 (m, 1H), 4.02 (br d,7=9.9 Hz, 2H), 3.71 (brt, 7=11.3 Hz, 2H), 2.24-2.14 (m, 2H), 2.11 -2.04 (m, 2H) 312 nh ₂ I ^n— ( 5 AyN'HN'JT 335.1 1.18 5 13.12 (brs, 1Н), 9.09 (brs, 1Н), 8.19 (d, 7=8.2 Hz, 1Н), 8.10 (brs, 1Н), 7.94-7.83 (m, 2Н), 6.82 (br s, 1Н) , 4.78 -4.67 (m, 1H), 4.11 (brdd, 7=11.5, 3.5 Hz, 1H), 3.94 (br dd, 7=11.4, 7.2 Hz, 1H), 3.82 -3.76 (m, 1H), 3.64 ( ddd, 7=11.3, 8.0, 3.4 Hz, 1H), 2.31-2.20 (m, 2H), 1.77-1.64 (m, 2H) 313 h ₂ n oh H ₃ c CH ₃ 0 N=/ hn Ji 337.1 0.99 5 13.23 - 13.03 (t, 1H), 8.83 (s, 1H), 8.19 (d, 7=8.0 Hz, 1H), 8.11 - 8.02 (t, 1H), 7.94 - 7.87 (t, 1H), 7.83 (dt , 7=4.3, 2.3 Hz, 1H), 6.82 (s, 1H), 5.04 (brs, 1H), 4.34 (s, 2H), 3.20 (brd,7=2.5 Hz, 2H), 0.90 (s, 6H) 314 NH _{2 H} q t o ....... < ~j _f /AZ N '- N. ,-Ή A ¹ HN J diastereomer 1 335.1 1.00 5 8.55 (s, 1H), 8.09 (brd, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.71 (brs, 1H), 7.64 (brd, 7=8.3 Hz, 1H), 7.21 -7.01 ( t, 2H), 6.75 (d, 7=1.9 Hz, 1H), 5.43 -5.24 (t, 1H), 4.65 4.58 (t, 1H), 4.34 (q, 7=6.9 Hz, 1H), 2.34 - 2.25 ( t, 1Н), 2.20-2.10 (t, 1Н), 2.09 2.00 (t, 1Н), 1.89-1.81 (t,

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2H), 1.69 - 1.58 (m, 1H) 315 NH ₂ but /A 1 L ^N AJ ζγ N N HN 'Ί enantiomer 1 335.2 1.01 5 8.52 (s, 1H), 8.09 (d, 7=8.3 Hz, 1H), 7.86 (s, 1H), 7.75 7.67 (m, 1H), 7.62 (br d, 7=8.0 Hz, 1H), 6.81 ( brs, 2H), 6.74 (d, 7=1.7 Hz, 1H), 5.37 (brs, 1H), 4.65-4.56 (m, 1H), 4.37-4.31 (m, 1H), 2.34-2.24 (m, 1H) , 2.182.09 (m, 1H), 2.08 -2.00 (m, 1H), 1.89 - 1.80 (m, 2H), 1.67 - 1.58 (m, 1H) 316 NH ₂ ho ^N N ζγΑ N HN -- ^J enantiomer 2 335.2 1.01 5 8.52 (s, 1H), 8.09 (d, 7=8.3 Hz, 1H), 7.86 (s, 1H), 7.75 7.66 (m, 1H), 7.62 (br d, 7=9.1 Hz, 1H), 6.82 ( br s, 2H), 6.74 (d, 7=1.7 Hz, 1H), 5.35 (brs, 1H), 4.64-4.58 (m, 1H), 4.37-4.31 (m, 1H), 2.33 -2.25 (m, 1H ), 2.182.08 (m, 1H), 2.08 -2.00 (m, 1H), 1.89 - 1.80 (m, 2H), 1.67 - 1.59 (m, 1H) 317 N ^h 2 ho аЖ) Αγ \—/ hn' j 349.1 1.09 5 8.48 (s, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.63 (brd, 7=8.0 Hz, 1H), 7.11 -6.94 (m, 2H), 6.75 (d, 7=2.1Hz, 1H), 5.00 (ddd, 7=6.0,4.1, 1.6Hz, 1H), 4.18 4.11 (m, 1H), 3.86 -3.78 (m, 1H) , 2.09 - 1.97 (m, 3H), 1.82 - 1.71 (m, 2H), 1.44 - 1.34 (m, 3H) 318 Y but N'^;'A ^: \u003d Z 7 \ I [ N-f ) W r ^N '- ^J N ^Z „<Z HN enantiomer 1 349.3 1.10 5 8.45 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.87 (s, 1H), 7.75 7.66 (m, 1H), 7.61 (brd, 7=6.3 Hz, 1H), 6.86 (br s, 2H), 6.74 (d, 7=1.1 Hz, 1H), 4.96 (brd, 7=3.6 Hz, 1H), 4.18-4.10 (m, 1H), 3.85 3.79 (m, 1H), 2.09-1.97 ( m, 3H), 1.81 - 1.72 (m, 2H), 1.44 - 1.34 (m, 3H) 319 Y but I [N—\ > γζγΑ ⁴ — ^z .....AA HN. Ί enantiomer 2 349.2 1.10 5 8.45 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.86 (s, 1H), 7.75 7.65 (m, 1H), 7.63 - 7.58 (m, 1H), 6.83 (br s, 2H ), 6.74 (s, 1H), 4.96 (brd,7=1.7 Hz, 1H), 4.17-4.10 (m, 1H), 3.86-3.78 (m, 1H), 2.09-1.94 (m, 3H), 1.83 - 1.70 (m, 2H), 1.44-1.34 (m, 3H)

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320 h ₂ n L /~~N Г \ DE V HN I 365.2 1.00 δ 13.20 - 13.03 (m, IH), 8.91 (s, IH), 8.18 (d, 7=8.0 Hz, IH), 8.12-8.05 (m, IH), 7.94 -7.88 (m, IH), 7.88-7.80 (m, IH), 6.81 (s, IH), 5.10 (s, IH), 4.46 (s, 2H), 3.68-3.56 (m, 4H), 1.70-1.62 (m, 2H), 1.36 (br d, 7=13.2Hz, 2H) 321 nh ₂ jlj ⁿ N^A^ hn' J 297.1 1.03 δ 13.22 - 13.05 (m, IH), 8.95 (s, IH), 8.20 (d, 7=8.2 Hz, IH), 8.10 (brs, IH), 7.92 (br d, 7=7.2 Hz, IH), 7.85 (br s, IH), 6.82 (d, 7=1.8 Hz, IH), 4.99-4.81 (m, 4H) 322 ΝΈ _H _ CH _{3 N} A\ ³ AoCiz 1 / ^N - ^N hn' Ύ 337.1 1.09 δ 13.27-13.00 (m, IH), 8.85 (s, IH), 8.18 (d, 7=8.2 Hz, IH), 8.07 (brs, IH), 7.91 (br d,7=8.3 Hz, IH), 7.82 (brs, IH), 6.82 (d, 7=1.9 Hz, IH), 4.51 (s, 2H), 3.23 (s, 3H), 1.14 (s, 6H) 323 nh ₂ ho GA-o, ργ n' Ao ΝχΑζ hn' J 337.1 0.78 δ 8.58 (s, IH), 8.08 (d, 7=8.2 Hz, IH), 7.87 (s, IH), 7.71 (br s, IH), 7.65 (brd,7=7.8 Hz, IH), 7.14-6.97 (m, 2H), 6.76 (d,7=2.1 Hz, IH), 5.89 (brd, 7=3.7 Hz, IH), 5.04 -4.98 (m, IH), 4.54 (br s, IH), 4.29 (dd , 7=9.9.6.2 Hz, IH), 4.184.13 (m, 2H), 3.70 -3.65 (m, IH) 324 A ² ho Y' ΥΧΑΊ , ^! N ⁰ f jaj HN 'i enantiomer 1 337.2 0.74 δ 8.66 (brs, IH), 8.11 (d, 7=8.2 Hz, IH), 7.91 (brs, IH), 7.76 - 7.65 (m, 2H), 6.77 (s, IH), 5.03 (brs, IH), 4.55 (brs, IH), 4.31 -4.26 (m, IH), 4.18-4.13 (m, 2H), 3.70 -3.65 (m, IH) 325 nh ₂ ho A \ / A IN - ς । AAn' f Α.Α HN J enantiomer 2 337.1 0.75 6 8.71-8.60 (m, IH), 8.15 8.05 (m, IH), 7.91 (brs, IH), 7.82 - 7.60 (m, 2H), 6.78 (s, IH), 5.03 (brs, IH), 4.56 4.50 (m, IH), 4.31 -4.26 (m, IH), 4.21 -4.13 (m, 2H), 3.72 -3.65 (m, IH)

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326 nh ₂ n/ ^CH3 1 LM ^N CH ₃ j T ⁿ x/A hn' J 293.2 1.06 5 8.55 (s, 1H), 8.10 (d, 7=8.1 Hz, 1H), 7.88 (d, 7=1.1 Hz, 1H), 7.71 (brs, 1H), 7.64 (br d, 7=8.1 Hz, 1H ), 7.16-6.95 (m, 2H), 6.76 (d, 7=1.9Hz, 1H), 4.84-4.76 (m, 1H), 1.56 (d, 7=6.6Hz, 6H) 327 nh ₂ iSp ^N ^A nAA v° hn' J enantiomer 1 335.0 0.92 5 8.49 (s, 1H), 8.07 (d, 7=8.3 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.62 (brd, 7=8.0 Hz, 1H), 6.97 - 6.84 (m, 2H), 6.75 (d,7=1.7Hz, 1H), 4.43 (brd, 7=7.4Hz, 2H), 3.84 -3.78 (m, 1H), 3.75 -3.70 (m, 1H), 3.70 - 3.63 (m, 1H), 3.54 (brdd, 7=8.5, 5.5 Hz, 1H), 2.88 2.79 (m, 1H), 2.O3 - 1.94 (m, 1H), 1.73 - 1.63 (m, 1H) 328 nh ₂ rSf ^N nAA v° hn' j enantiomer 1 335.2 0.92 5 8.49 (s, 1H), 8.07 (d, 7=8.3 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.62 (brd,7=9.1 Hz, 1H), 6.96 - 6.84 (m, 2H), 6.75 (d,7=1.7Hz, 1H), 4.42 (brd, 7=7.7Hz, 2H), 3.83 - 3.78 (m, 1H), 3.74 -3.70 (m, 1H), 3.69 - 3.63 (m, 1H), 3.56-3.52 (m, 1H), 2.92-2.80 (m, 1H), 2.02-1.94 (m, 1H), 1.73-1.63 (m, 1H) 329 nh ₂ aX% iPY ⁿ /-0 A O HN J 335.3 0.97 5 8.49 (s, 1H), 8.06 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.74 7.68 (m, 1H), 7.61 (brd, 7=7.6 Hz, 1H), 6.92 (br s, 2H), 6.75 (d, 7=1.4 Hz, 1H), 4.55 -4.49 (m, 1H), 4.44 4.37 (m, 1H), 4.32-4.25 (m, 1H), 3.77 (q, 7=7.0 Hz, 1H), 3.69 -3.63 (m, 1H), 2.071.98 (m, 1H), 1.85 - 1.73 (m, 2H), 1.69 - 1.60 (m, 1H) 330 NH ₂ ΔΑ / ⁰ Nxkk xA hn' J 335.2 0.96 5 8.89 (s, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.05 (s, 1H), 7.91 (br d, 7=7.9 Hz, 1H), 7.81 (brs, 1H), 6.82 (s , 1H), 4.58 (brdd, 7=14.0, 2.7 Hz, 1H), 4.50 4.41 (m, 1H), 4.33 -4.26 (m, 1H), 3.80 -3.68 (m, 2H), 2.09 -2.01 (m 1H), 1.86 - 1.75 (m, 2H), 1.69 - 1.60 (m, 1H)

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331 nh ₂ )—OCH _{3 N} 1J ^НзС HN'Jj 323.3 0.95 δ 13.18 - 13.05 (m, 1H), 8.86 (brs, 1H), 8.18 (brd, 7=8.3Hz, 1H), 8.10 (brd,7=1.1Hz, 1H), 7.94 -7.83 (m, 2H), 6.81 (br s, 1H), 4.59 (br dd, 7=14.0, 2.5 Hz, 1H), 4.46 (br dd, 7=14.3, 7.2 Hz, 1H), 3.89 -3.83 (m, 1H), 3.23 (s , 3H), 1.15 (br d, 7=6.3 Hz, ZN) 332 ^ ^Η 2 H ₃ C OH ^N hn' y 322.9 1.07 δ 13.23 - 13.01 (m, 1H), 8.88 (s, 1H), 8.19 (d, 7=8.0 Hz, 1H), 8.10 (brs, 1H), 7.92 (br d, 7=7.4 Hz, 1H), 7.84 (br s, 1H), 6.82 (s, 1H), 4.90 - 4.82 (m, 1H), 4.52 (dd, 7=13.6, 6.2 Hz, 1H), 4.30 (dd, 7=13.6, 7.8 Hz, 1H) , 3.38-3.31 (m, 2H), 2.30-2.22 (m, 1H), 0.86 (d, 7=6.6 Hz, ZN) 333 h ₂ n _n X^X^^°^cf ₃ 4 )=N O N=/ nm'U 377.1 1.32 δ 13.25 - 13.02 (m, 1H), 8.91 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.08 (brs, 1H), 7.92 (br d, 7=8.3 Hz, 1H), 7.83 (br s, 1H), 6.82 (d, 7=1.9 Hz, 1H), 4.71 (t, 7=4.8 Hz, 2H), 4.13 4.06 (m, 4H) 334 ΞΕ Z L>μ V- \/I )----( No. ABOUT z I ω 279.1 0.90 δ 8.50 (s, 1H), 8.13-8.05 (m, 1H), 7.87 (s, 1H), 7.71 (brd, 7=1.0 Hz, 1H), 7.64 (br dd, 7=5.3, 1.6 Hz, 1H) , 7.11 6.92 (m, 2H), 6.75 (br d, 7=2.1 Hz, 1H), 4.43 (q, 7=7.2 Hz, 2H), 1.51 (t, 7=7.3 Hz, ZN) 335 nh ₂ XA- 355.0 1.17 δ 13.19-13.04 (m, 1H), 8.88 (brs, 1H), 8.18 (d,7=8.2 Hz, 1H), 8.09 (brs, 1H), 7.957.83 (m, 2H), 6.81 (s, 1H ), 4.65 (br d, 7=6.8 Hz, 2H), 2.83 -2.67 (m, 3H), 2.60 2.52 (m, 2H) 336 nh _{2 N} X ^OCH3 1 1 ^N —\ Ι^γ^Ν CH ₃ HN J 323.2 0.98 δ 8.54 (s, 1H), 8.11 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H), 7.71 (s, 1H), 7.65 (br d, 7=8.2 Hz, 1H), 6.76 (d , 7=2.1 Hz, 1H), 4.87-4.79 (m, 1H), 3.80 3.74 (m, 1H), 3.69 -3.65 (m, 1H), 3.20 (s, 3H), 1.53 (d, 7=6.7 Hz , ZN)

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337 NH ₂ ^OCH3 1 X ^Ν \ CH ₃ HN T enantiomer 1 323.3 1.13 δ 8.51 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (br s, 1H), 7.62 (brd, 7=8.0 Hz, 1H), 6.97-6.81 (m, 2H), 6.75 (s, 1H), 4.87 - 4.80 (m, 1H), 3.80 -3.74 (m, 1H), 3.69 (br dd, 7=10.5, 3.9 Hz, 1H), 3.22 (s, 3H), 1.54 (d, 7=6.9Hz, 3H) 338 nh ₂ ^och ₃ 1 Г n—\ ^N< CH ₃ hn' J \==J enantiomer 2 323.1 1.15 δ 8.51 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (br s, 1H), 7.62 (brd,7=8.5 Hz, 1H), 6.89 (br s, 2H), 6.75 (d, 7=1.8 Hz, 1H), 4.88 -4.80 (m, 1H), 3.79 -3.74 (m, 1H), 3.68 (brdd, 7=10.3, 4.1 Hz, 1H), 3.22 (s, 3H), 1.54 (brd,7=6.8Hz, 3H) 339 I o Vz o CM ) ( o'z I 335.3 1.04 δ 13.49-13.01 (m, 1H), 9.69 - 9.40 (m, 1H), 8.96 - 8.92 (m, 1H), 8.90-8.71 (m, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.06 (brs, 1H), 7.91 (brd,7=8.2 Hz, 1H), 7.83 (brs, 1H), 6.81 (d, 7=1.7 Hz, 1H), 5.28-5.20 (m, 1H), 5.10-4.89 ( m, 1H), 4.44 (brs, 1H), 2.47-2.38 (m, 1H), 2.28-2.10 (m, 3H), 2.04-1.96 (m, 1H), 1.721.64 (m, 1H) 340 NH ₂ ho ΐ dX xv ^N hn' I _o diastereomer 2 335.2 0.96 δ 8.65 (s, 1H), 8.10 (d, 7=8.1 Hz, 1H), 7.90 (br s, 1H), 7.77 -7.63 (m, 2H), 7.31 -7.05 (m, 2H), 6.77 (d, 7=1.8 Hz, 1H), 5.03 (brs, 1H), 4.864.76 (m, 1H), 4.29 (br s, 1H), 2.31-2.20 (m, 2H), 2.04 1.95 (m, 2H), 1.80 - 1.67 (m, 2H) 341 nh ₂ A _ _ OH Ϊ jj ^N hn' j enantiomer 1 335.1 0.91 δ 8.61 (s, 1H), 8.06 (d, 7=8.3 Hz, 1H), 7.87 (s, 1H), 7.73 7.67 (m, 1H), 7.62 (br d, 7=8.8 Hz, 1H), 6.96 - 6.87 (m, 2H), 6.75 (d, 7=1.7 Hz, 1H), 5.04-4.95 (m, 1H), 4.29 4.23 (m, 1H), 2.32-2.15 (m, 3H), 1.98 (dt, 7 =13.1, 6.4 Hz, 1H), 1.89 - 1.77 (m, 2H)

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342 ην' J νη ₂ Α _ _ .OH ϊ ΎΗΪ Cj ^Ν diastereomer 2 335.3 0.91 δ 8.61 (s, 1H), 8.07 (d, 7=8.0 Hz, 1H), 7.86 (s, 1H), 7.70 (br s, 1H), 7.62 (d, 7=8.3 Hz, 1H), 6.97 - 6.86 (m, 2H), 6.75 (s, 1H), 5.02 -4.94 (m, 1H), 4.29-4.23 (m, 1H), 2.30 2.13 (m, 3H), 1.97 (dt, 7=12.7, 6.2 Hz, 1H), 1.88 1.74 (m, 2H) 343 N^. ην Ύ —J ΝΗο SP, G hc\j ³ Ϊ EMI Khd ^N 349.3 1.16 δ 8.93 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.09 (brs, 1H), 7.92 (brd,7=8.3 Hz, 1H), 7.87 7.80 (m, 1H), 6.81 (s , 1H), 5.18 (brs, 1H), 4.74 (t, 7=7.3 Hz, 1H), 2.47 - 2.32 (m, 2H), 1.98 - 1.78 (m, 4H), 0.82 (s, 3H) 344 ην' J \ -J l ^{2 Η0} Α ϊ jAnAA Xd ^Ν enantiomer 1 349.1 1.10 δ 8.75 (brs, 1H), 8.15 (d, 7=8.2 Hz, 1H), 7.98 (br d, 7=1.5 Hz, 1H), 7.79 (br d, 7=8.5 Hz, 2H), 6.79 (d, 7=1.7 Hz, 1H), 5.17 (brs, 1H), 4.7O (brt, 7=7.2 Hz, 1H), 2.46 2.30 (m, 2H), 1.97- 1.77 (m, 4H), 0.80 (s, 3H ) 345 Ν^, ην' ] NH? pu f HC\j ³ 1 jA ^N \ J ^N enantiomer 2 349.2 1.10 δ 8.64 (s, 1H), 8.11 (d, 7=8.1 Hz, 1H), 7.93 (s, 1H), 7.77 7.68 (m, 2H), 6.77 (d, 7=1.8 Hz, 1H), 5.10 (brs , 1H), 4.68 (brt, 7=7.1 Hz, 1H), 2.472.31 (m, 2H), 1.98 - 1.76 (m, 4H), 0.79 (s, 3H) 346 Ν^ζ ΗΝ J U ^H 2 n ₃ s) - basic ₃ 1 L, ^N - '(Y-enantiomer 1 323.1 1.02 δ 8.54 (brs, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.92 (br s, 1H), 7.81 -7.62 (m, 2H), 6.77 (s, 1H), 4.52 (br dd, 7 =14.2, 3.6Hz, 1H), 4.41(dd, 7=14.0, 7.1Hz, 1H), 3.84(brdd, 7=10.3, 6.4Hz, 1H), 3.21(s, 3H), 1.14(d, 7= 6.3 Hz, VN) 347 Ν^ ην' J U ^H 2 n ₃ with Voch ₃ 1 I /N- iQi ^N enantiomer 2 323.1 1.02 δ 8.45 (s, 1H), 8.07 (d, 7=8.0 Hz, 1H), 7.87 (s, 1H), 7.75 7.68 (m, 1H), 7.61 (brd, 7=7.2 Hz, 1H), 6.89 (br s, 2H), 6.75 (s, 1H), 4.53 - 4.46 (m, 1H), 4.39 (brdd,7=13.9, 6.7 Hz, 1H), 3.87 -3.79 (m, 1H), 3.21 (s, 3H) , 1.14 (brd, 7=6.3 Hz, ZN)

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348 nh ₂ ^CF ₃ 1 r ^N n-^A^A hn' j 347.2 1.22 δ 13.54 - 13.02 (m, 1H), 9.00 (s, 1H), 8.21 (brd, 7=8.3 Hz, 1H), 8.16-8.08 (m, 1H), 7.93 (brd, 7=8.0 Hz, 1H), 7.907.83 (m, 1H), 6.82 (br s, 1H), 4.83 (brt,7=6.5 Hz, 2H), 3.15 -3.05 (m, 2H) 349 nh ₂ Ϊ lX Αγ n A .JU x hn T ^F 345.2 1.04 δ 13.52 - 12.80 (m, 1H), 8.52 (s, 1H), 8.08 (d, 7=8.1 Hz, 1H), 7.88 (brs, 1H), 7.83 7.60 (m, 2H), 7.12-6.95 (m, 2H), 6.78 - 6.74 (m, 1H), 6.66 (t, 7=75.2Hz, 1H), 4.69 (brt, 7=4.6Hz, 2H), 4.33 (t, 7=4.8Hz, 2H) 350 ^h _{2 n} 377.3 1.35 δ 13.09-12.78 (m, 1H), 8.53 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.90 (brs, 1H), 7.837.60 (m, 2H), 7.25 - 6.98 (m , 2H), 6.75 (s, 1H), 4.54 (brt, 7=6.9Hz, 2H), 4.14 (brt, 7=6.1Hz, 2H), 2.34 (brt, 7=6.5Hz, 2H) 351 h ₂ n V / ^N O N=Z HN^ 323.3 0.97 δ 8.49 (s, 1H), 8.08 (d, 7=8.3 Hz, 1H), 7.88 (s, 1H), 7.73 7.69 (m, 1H), 7.63 (br d, 7=8.0 Hz, 1H), 7.05 - 6.94 (m, 2H), 6.75 (d, 7=1.7 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.43 (br t, 7=6.9 Hz, 2H), 1.99-1.92 (m, 2H), 1.47- 1.39 (m, 2H) 352 h ₂ n o HN \ 363.2 1.23 δ 13.18 - 12.83 (m, 1H), 8.59 (s, 1H), 8.10 (brd,7=8.3 Hz, 1H), 7.90 (brs, 1H), 7.837.62 (m, 2H), 7.39 - 7.05 (m , 2H), 6.76 (s, 1H), 4.79 (br d, 7=4.1 Hz, 2H), 4.59 (brt, 7=4.4 Hz, 2H) 353 H ₂ N ^N / Kn Λ ^OH o Ν=Λ HN^ 335.2 0.88 δ 13.19-13.05 (m, 1H), 8.94 (s, 1H), 8.19 (brd,7=8.3 Hz, 1H), 8.11-8.02 (m, 1H), 7.95-7.88 (m, 1H), 7.87-7.77 (m, 1H), 6.81 (brs, 1H), 4.93 (s, 1H), 4.45 (s, 2H), 3.21 (br s, 2H), 0.74 (br s, 2H), 0.58 (br s, 2H)

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354 H ₂ N f ⁿ /J=n ^f o N=/ HN z) 329.3 1.13 δ 13.19-13.07 (m, 1H), 8.94 (s, 1H), 8.20 (brd,7=8.0 Hz, 1H), 8.14-8.04 (m, 1H), 7.92 (brd,7=8.3 Hz, 1H), 7.88 7.79 (m, 1H), 6.81 (s, 1H), 6.39-6.14 (m, 1H), 4.68 (br t, 7=6.7 Hz, 2H), 2.64-2.55 (m, 2H) 355 H ₂ N n NM II V _rH V/- ^N n. _q / ^Сн з О N=Z HN^ 347.0 1.04 6 13.33 - 13.02 (m, 1H), 9.12 (s, 1H), 8.15 (br d, 7=8.0 Hz, 1H), 8.12-8.07 (m, 1H), 7.90 (brd,7=7.2 Hz, 1H) , 7.87 7.81 (m, 1H), 6.81 (s, 1H), 5.99 (s, 2H), 2.58(s, 3H) 356 I O I co A\/° z o OJ ) ( *vo About z I 337.2 1.19 δ 13.19-12.72 (m, 1H), 8.57 - 8.48 (m, 1H), 8.09 (brd, 7=8.0 Hz, 1H), 7.91 (br s, 1H), 7.82 - 7.59 (m, 2H), 7.38 - 7.01 (m, 2H), 6.76 (s, 1H), 4.70 (br s, 1H), 4.45 (br dd, 7=12.9, 6.6 Hz, 1H), 4.33 (br dd, 7=13.9, 7.3 Hz, 1H ), 2.08 - 1.98 (m, 1H), 1.41 - 1.32 (m, 1H), 1.30 - 1.20 (m, 1H), 0.90 (brt, 7=7.4 Hz, ZN); two CH protons are not visible, probably due to overlap with the suppressed water peak. 357 h ₂ n ^N \ ON L NH O N=/ HN^/ 331.2 1.00 δ 13.31 - 12.92 (m, 2H), 8.89 (s, 1H), 8.19 (brd,7=8.0Hz, 1H), 8.14-8.05 (m, 1H), 7.91 (brd,7=8.0Hz, 1H), 7.84 (br d, 7=1.7 Hz, 1H), 7.76 (br d, 7=1.9 Hz, 1H), 6.81 (s, 1H), 6.38 (s, 1H), 5.70 (brs, 2H) 358 H ₂ N ^N \ ON L NH /=/ N w N=/ HN^) 330.9 1.04 δ 8.40 (s, 1H), 8.08 (d, 7=8.1 Hz, 1H), 7.86 (d, 7=1.1 Hz, 1H), 7.76 (br s, 2H), 7.70 (br s, 1H), 7.62 ( br d, 7=7.9 Hz, 1H), 7.04 - 6.86 (m, 2H), 6.75 (d, 7=2.0 Hz, 1H), 5.52 (s, 2H) 359 nh ₂ ajO Гт mo ,ν^ΓΓ Гт HN Ύ ^ ^ΝΗ 331.2 0.99 δ 8.66 - 8.62 (m, 1H), 8.36 (br d,7=8.5 Hz, 1H), 8.16 (brs, 1H), 7.96 (br d, 7=8.6 Hz, 1H), 7.84 (br s, 1H) , 7.56 (br s, 2H), 6.85 (d, 7=1.8 Hz, 1H), 5.93 (s, 2H)

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360 „ζ-, ζ \ V/ ¹ X 343.2 1.00 5 13.37 - 12.95 (m, 1H), 9.85 - 9.60 (m, 1H), 9.22 (dd, 7=4.3, 1.9 Hz, 1H), 9.13 9.10 (m, 1H), 9.00 - 8.80 (m, 1H), 8.14 (d, 7=8.3 Hz, 1H), 8.07 (brs, 1H), 7.89 (brd, 7=8.5 Hz, 1H), 7.82 (br s, 1H), 7.79 - 7.72 (m, 2H), 6.81 ( d, 7=1.9 Hz, 1H), 6.10-6.04 (m, 2H) 361 η ₂ ν ν=\ ΧΡ Ν ΌΑ _ζ Ν η Ν> Ν Ο Ν=Ζ ^η ν'Ρ 344.9 0.87 5 8.95 - 8.91 (m, 1H), 8.85 8.82 (m, 1H), 8.16 (d, 7=8.2 Hz, 1H), 8.09 (brs, 1H), 7.92 (brd,7=8.2 Hz, 1H), 7.84 (br s, 1H), 7.38 (br s, 1H), 6.81 (d, 7=2.1 Hz, 1H), 4.82 (brt, 7=6.4 Hz, 2H), 3.39 -3.34 (m, 2H) 362 η ₂ ν kA Ο S ην A 348.1 1.08 5 13.28 - 13.04 (m, 1H), 9.77 -9.54 (m, 1H), 9.14 (brd, 7=1.6 Hz, 1H), 8.99 (s, 1H), 8.95 - 8.80 (m, 1H), 8.17 (d , 7=8.2 Hz, 1H), 8.08 (brs, 1H), 7.93 - 7.87 (m, 2H), 7.84 (brs, 1H), 6.82 (d,7=1.9 Hz, 1H), 5.87 (br s, 2H ) 363 νη ₂ zy „ΡρΝΗ fSr ^Ν Ν-ΡΡ ην' j 370.2 0.89 5 8.95 (s, 1H), 8.24 (d, 7=8.3Hz, 1H), 8.08 (s, 1H), 7.93 (dd, 7=8.3, 1.1Hz, 1H), 7.83 (d, 7=2.2Hz, 1H), 6.83 (d, 7=2.2 Hz, 1H), 4.88 - 4.80 (m, 1H), 4.73 (dd, 7=14.3, 8.5 Hz, 1H), 4.29-4.21 (m, 1H), 2.79 -2.69 (m, 1H), 2.44-2.33 (m, 1H); two CH protons are not visible, probably due to overlap with the suppressed water peak. 364 ^ ^Η 2 HQ OH ϊ ry ^Ν NxZp ην' J 325.1 0.91 5 13.38 - 13.04 (br, 1H), 8.92 (s, 1H), 8.19 (brd, 7=8.2 Hz, 1H), 8.12 (brs, 1H), 7.92 (br d, 7=8.1 Hz, 1H), 7.87 (br s, 1H), 6.82 (brs, 1H), 5.29 (br d,7=5.2Hz, 1H), 4.96 (brt, 7=5.1Hz, 1H), 4.61 (dd, 7=13.8, 2.6Hz, 1H), 4.35 (dd, 7=13.7, 8.6 Hz, 1H), 3.94 (br s, 1H), 3.51 -3.46 (m, 2H) 365 I o °*l ζ o Chu About ζ t 324.9 0.92 5 13.27-13.06 (m, 1H), 8.94 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.12 (brs, 1H), 7.92 (br d, 7=7.7 Hz, 1H), 7.85 (br d, 7=6.6 Hz, 1H), 6.81 (d, 7=1.4 Hz, 1H), 5.27 (brd, 7=3.6 Hz,

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1H), 4.93 (brd,7=4.4Hz, 1H), 4.61 (dd, 7=13.8, 3.0Hz, 1H), 4.36 (dd, 7=13.8, 8.5Hz, 1H), 3.94 (brd,7=5.0 Hz, 1H), 3.52 -3.46 (m, 1H), 3.43 -3.38 (m, 1H) 366 NO CH ₃ ij ^N N^/XV HN J 323.3 0.92 5 8.89 (s, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.07 (brs, 1H), 7.92 (brd,7=8.5 Hz, 1H), 7.83 (br s, 1H), 6.83 (s , 1H), 4.49 (dd, 7=13.7, 2.7 Hz, 1H), 4.32 (dd, 7=13.7, 8.2 Hz, 1H), 3.86 (br d, 7=1.8 Hz, 1H), 1.61 - 1.47 (m , 1H), 1.42 (dt, 7=13.9, 7.1 Hz, 1H), 0.95 (t, 7=7.5 Hz, 3H) 367 ^2 HO CH ₃ Ϊ jYnA JlJ ^N N^/\V HN J 323.1 0.98 5 8.90 (brd, 7=2.4 Hz, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.08 (br s, 1H), 7.93 (d, 7=7.9 Hz, 1H), 7.84 (s, 1H ), 6.84 (d, 7=2.3 Hz, 1H), 4.57 - 4.45 (m, 1H), 4.32 (brdd, 7=13.6, 8.1 Hz, 1H), 3.95 - 3.82 (m, 1H), 1.51 (brdd, 7=13.3, 6.2 Hz, 1H), 1.44 - 1.33 (m, 1H), 0.96 (t, 7=7.3 Hz, 3H) 368 ^2 HQ CH ₃ Ϊ ij ^N HN J 323.1 0.98 5 8.90 (brd, 7=2.4 Hz, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.08 (br s, 1H), 7.93 (d, 7=7.9 Hz, 1H), 7.84 (s, 1H ), 6.84 (d, 7=2.3 Hz, 1H), 4.57 - 4.45 (m, 1H), 4.32 (brdd,7=13.6, 8.1 Hz, 1H), 3.95 - 3.82 (m, 1H), 1.51 (brdd, 7=13.3, 6.2 Hz, 1H), 1.44 - 1.33 (m, 1H), 0.96 (t, 7=7.3 Hz, 3H) 369 Iz QmV \/T ) ( GO ABOUT 'z about T co 309.3 0.98 Ή NMR (400 MHz, DMSOd ₆ )5 8.98 (s, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.13 (s, 1H), 7.93 (dd, 7=8.2, 1.4 Hz, 1H), 7.86 (d, 7=2.1Hz, 1H), 6.83 (d, 7=2.2Hz, 1H), 4.49 (dd, 7=13.6, 3.4Hz, 1H), 4.34 (dd, 7=13.7, 7.8Hz, 1H ), 4.224.06 (m, 1H), 1.20-1.17 (m, 3H) 370 NH ₂ HQ mUM MH ₃ 1 1 ^N - HN J 309.1 0.98 5 9.76 -9.55 (m, 1H), 8.978.89 (m, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.10 (brs, 1H), 7.93 (brd,7=8.3 Hz, 1H), 7.85 (br s, 1H), 6.83 (d, 7=2.0Hz, 1H), 4.48 (brdd,7=13.3, 3.1Hz, 1H), 4.32 (brdd,7=13.7, 8.1Hz, 1H), 4.20 - 4.06 (m,

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1Н), 1.18 (d, 7=6.2 Hz, ZN) 371 ^Η Λ zx CH ₃ N-^Xx, 1 J ⁰ CH ₃ O Ν=/ ΗΝ^ 367.4 1.33 δ 9.80 -9.56 (m, 1H), 8.978.87 (m, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.09 (brs, 1H), 7.93 (brd,7=7.9 Hz, 1H), 7.84 (br s, 1H), 6.83 (d, 7=2.1 Hz, 1H), 4.63-4.54 (m, 1H), 4.39 (brdd, 7=13.8, 8.0 Hz, 1H), 4.13-3.98 (m, 1H ), 3.51 3.30 (m, 2H), 1.12 (brt, 7=5.6 Hz, 6H) 372 HO OCH ₃ Ϊ XdG ^N ΝχΑΑ hn' j 339.0 1.27 δ 8.87 (s, 1H), 8.20 (d, 7=8.2 Hz, 1H), 8.13 - 8.03 (m, 1H), 7.90 (brd,7=5.8 Hz, 1H), 7.88 - 7.80 (m, 1H), 6.82 (d, 7=1.4 Hz, lH), 4.56(dd, 7=13.8, 3.2 Hz, 1H), 4.39 (dd, 7=13.8, 8.2 Hz, 1H), 4.164.04 (m, 1H), 3.45 -3.36(m, 2H), 3.33(s, 3H) 373 ^2 HQ OCH ₃ XdG ^N ΝχΑΑ hn' j 339.2 1.22 6 8.85 (brs, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.07 (br s, 1H), 7.95 - 7.72 (m, 2H), 6.81 (s, 1H), 4.56 (dd, 7= 13.9, 3.2 Hz, 1H), 4.39 (dd, 7=13.7, 8.2 Hz, 1H), 4.11 (brs, 1H), 3.49 -3.35 (m, 2H), 3.31 (s, 3H)) 374 ^ ^Η 2 but sn ₃ / \ 1 L ^sn z ^Ν ΗΝ Ύ 337.1 1.37 6 9.74-9.55 (m, 1H), 8.998.81 (m, 2H), 8.21 (d, 7=8.3 Hz, 1H), 8.10 (brs, 1H), 7.93 (d, 7=8.6 Hz, 1H), 7.84 (brs, 1H), 6.83 (d, 7=2.2 Hz, 1H), 4.53 (brd,7=13.3 Hz, 1H), 4.40-4.28 (m, 1H), 3.793.67 (m, 1H), 1.77 - 1.64 (m, 1H), 0.97 (br dd, 7=12.6, 6.8 Hz, 6H) 375 ΆΝ. CH ₃ H^O^T^o+ ^CH 3 A/ but CH ₃ O Ν=/ ΗΝ,χ 381.3 1.46 6 8.89 (s, 1H), 8.20 (d, 7=8.5 Hz, 1H), 8.08 (brd,7=4.3 Hz, 1H), 7.98 - 7.89 (m, 1H), 7.88 - 7.78 (m, 1H), 6.83 (s, 1H), 4.62-4.53 (m, 1H), 4.37 (dd, 7=13.9, 8.1 Hz, 1H), 4.01 (br d,7=3.4 Hz, 1H), 3.61 (brd, 7=6.7 Hz, 1H), 3.39 (brdd, 7=8.7, 4.7 Hz, 1H), 3.33 3.24 (m, 1H), 1.17 (s, 9H)

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376 hn't N Ju N ^H 2 HO f y^N enantiomer 1 327.3 0.78 δ 13.45 - 12.78 (m, 1H), 8.48 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.72 (brd, 7=6.6 Hz, 1H), 7.62 ( br d, 7=7.7 Hz, 1H), 6.91 (brs, 2H), 6.75 (d, 7=1.6 Hz, 1H), 5.76 -5.59 (m, 1H), 4.58 4.32 (m, 4H), 4.26-4.16 (m, 1H) 377 hn' T—J N A ho f nH ^Z Y^N enantiomer 2 327.3 0.78 δ 13.35 - 12.64 (m, 1H), 8.48 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.86 (d, 7=1.3 Hz, 1H), 7.71 (brs, 1H), 7.62 ( brd, 7=8.5 Hz, 1H), 6.90 (brs, 2H), 6.75 (d, 7=2.1Hz, 1H), 5.85 -5.54 (m, 1H), 4.57 4.33 (m, 4H), 4.26-4.16 ( m, 1H) 378 N^xhn' J N* A ^ ⁿ 2 HO CF ₃ nH ^f γ^N enantiomer 1 377.1 1.21 δ 8.51 (s, 1H), 8.09 (d, 7=8.0 Hz, 1H), 7.88 (s, 1H), 7.76 7.68 (m, 1H), 7.67 - 7.63 (m, 1H), 7.18-7.00 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H), 5.73 -5.62 (m, 1H), 4.50 (brdd, 7=12.9, 2.8 Hz, 1H), 4.39-4.28 (m, 2H), 2.66 - 2.55 (m, 1H), 2.45 - 2.34 (m, 1H) 379 N-xhn'Ύ N' A U ^H 2 HO CF ₃ γ ^ N enantiomer 2 377.1 1.26 6 8.49 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.87 (s, 1H), 7.75 7.66 (m, 1H), 7.63 (brd, 7=7.2 Hz, 1H), 6.95 (br s, 2H), 6.75 (d, 7=1.9Hz, 1H), 5.62 (brd,7=5.8Hz, 1H), 4.51 (dd, 7=13.2, 3.0Hz, 1H), 4.40 - 4.27 (m, 2H ), 2.68 2.55 (m, 1H), 2.47–2.34 (m, 1H) 380 N^/ hn' j N' Ό Y ^H 2 but CN £ N^ γ^N 334.1 0.71 δ 9.01 (s, 1H), 8.19 (d, 7=8.3 Hz, 1H), 8.08 (brs, 1H), 7.90 (brd,7=6.1 Hz, 1H), 7.867.80 (m, 1H), 6.81 ( d, 7=2.2Hz, 1H), 5.46 (brt, 7=5.1Hz, 1H), 5.08 (quin, 7=6.4Hz, 1H), 3.89 -3.86 (m, 2H), 3.30 (brd,7=6.9 Hz, 2H) 381 N^ ^HN 'Jj N' b ^ ^H 2 HQ CN V ^/ Y^N 333.9 1.05 δ 9.06 (s, 1H), 8.21 (d, 7=8.3 Hz, 1H), 8.11 (brs, 1H), 7.94 (brd,7=8.3 Hz, 1H), 7.877.80 (m, 1H), 6.82 ( d, 7=2.2 Hz, 1H), 5.49 (brs, 1H), 5.12 -5.05 (m, 1H), 3.91 -3.82 (m, 2H), 3.30 (d, 7=7.2 Hz, 2H)

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382 HQ nh ₂ Ay A ⁿ n^A^A hn' j 349.9 0.48 δ 8.51 (s, 1H), 8.07 (d, 7=8.3 Hz, 1H), 7.87 (d, 7=1.4 Hz, 1H), 7.71 (s, 1H), 7.62 (dd, 7=8.1, 1.2 Hz, 1H), 7.10 6.94 (m, 2H), 6.75 (d, 7=2.2 Hz, 1H), 4.46 - 4.35 (m, 2H), 4.22-4.18 (m, 1H), 2.94 (dd, 7=11.0, 5.8 Hz, 1H), 2.7O (dd, 7=11.1, 4.0 Hz, 1H), 2.102.02 (m, 1H), 1.41 (dt, 7=12.9, 5.4 Hz, 1H) 383 h ₂ n La ⁰ N^A ⁷ HN \ 362.0 0.95 δ 13.29-13.10 (m, 1H), 9.73 - 9.50 (m, 1H), 8.88 (s, 1H), 9.02 - 8.84 (m, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.11 (brs , 1H), 7.92 (brd, 7=8.0 Hz, 1H), 7.89 -7.82 (m, 1H), 6.81 (d, 7=1.7 Hz, lH), 4.66(t, 7=5.8 Hz, 2H), 3.70 (t, 7=5.8Hz, 2H), 3.33 - 3.29 (m, 2H), 2.15 -2.10 (m, 2H), 1.91 (quin, 7=7.5Hz, 2H) 384 I z £> 4h z% ^s zl„ o 348.1 0.96 δ 8.45 (s, 1H), 8.08 (d, 7=8.3 Hz, 1H), 7.88 (brs, 1H), 7.80 (s, 1H), 7.71 (brs, 1H), 7.62 (brd, 7=8.3 Hz, 1H), 7.036.90 (m, 2H), 6.75 (d, 7=1.1 Hz, 1H), 4.50 - 4.42 (m, 2H), 4.12-4.05 (m, 1H), 2.182.10 (m, 1H) , 2.09–2.03 (m, 2H), 2.02–1.84 (m, 1H). 385 o ^~z^ z _χ o az I 348.0 0.92 6 8.45 (s, 1H), 8.08 (d, 7=8.0 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.74 - 7.66 (m, 1H), 7.65 -7.59(m, 1H ), 6.88 (br s, 2H), 6.75 (d, 7=1.9 Hz, 1H), 4.49-4.41 (m, 2H), 4.124.06 (m, 1H), 2.19-2.09 (m, 1H), 2.08 -2.03 (m, 2H), 1.93 - 1.84 (m, 1H) 386 NH ₂ N/ ^F nA ^f xP' ^N nAA hn' J 341.0 1.09 δ 13.12-12.81 (m, 1H), 8.62 (brs, 1H), 8.10 (d,7=8.2 Hz, 1H), 7.92 (brs, 1H), 7.857.62 (m, 2H), 7.57-7.12 (m , 2H), 6.77 (d, 7=1.3 Hz, 1H), 4.66-4.60 (m, 1H), 4.594.53 (m, 1H), 2.47-2.38 (m, 1H), 1.84 - 1.73 (m, 1H ), 1.67 - 1.57 (m, 1H)

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387 H ₂ N N C H 3 / \u003d 7 ° ⁰ O nn 371.2 1.09 5 8.93 (s, 1H), 8.62 (d, 7=2.5 Hz, 1H), 8.28 (d, 7=8.5 Hz, 1H), 8.16 (d, 7=1.9 Hz, 1H), 7.96 (dd, 7= 8.7, 2.1 Hz, 1H), 7.85 (d, 7=1.4 Hz, 1H), 6.65 6.62 (m, 1H), 4.64 (t, 7=6.9 Hz, 2H), 3.24-3.17 (m, 2H), 3.01 (s, 3H), 2.39 (quin, 7=7.3Hz, 2H) 389 y2 H ₃ CO OH 1Y ^N 339.3 0.86 5 8.88 (s, 1H), 8.58 (d, 7=2.2 Hz, 1H), 8.26 (d, 7=8.6 Hz, 1H), 8.11 (s, 1H), 7.93 (brd, 7=8.6 Hz, 1H) , 7.84 (s, 1H), 6.63 (t, 7=1.9 Hz, 1H), 5.154.99 (m, 1H), 4.64 (dd, 7=13.9,3.1 Hz, 1H), 4.50 (dd, 7=14.2 , 7.6 Hz, 1H), 3.723.65 (m, 1H), 3.54 -3.50 (m, 2H), 3.24 (s, 3H) 389 y2 but it is Ϊ 1Y ^N 325.2 0.95 5 8.56 (d, 7=2.2 Hz, 1H), 8.52 (s, 1H), 8.14 (d, 7=8.5 Hz, 1H), 7.87 (d, 7=2.2 Hz, 1H), 7.76 (d, 7= 1.4 Hz, 1H), 7.68 (dd, 7=8.5, 2.2 Hz, 1H), 7.20 7.10 (m, 2H), 6.56 -6.55 (m, 1H), 5.17 (d, 7=5.2 Hz, 1H), 4.90 -4.83 (m, 1H), 4.56 (dd, 7=13.5, 3.3Hz, 1H), 4.26 (dd, 7=13.6, 8.4Hz, 1H), 3.95 (br d, 7=2.8Hz, 1H), 3.49 -3.43(m, 2H) 390 nh _{2 f} LL /j 315.2 1.11 5 8.59 (s, 1H), 8.56 (d, 7=2.2 Hz, 1H), 8.14 (d, 7=8.3 Hz, 1H), 7.87 (d, 7=1.9 Hz, 1H), 7.77 (s, 1H) , 7.69 (dd, 7=8.5, 1.9 Hz, 1H), 7.24 - 7.08 (m, 2H), 6.55 (d, 7=1.7 Hz, 1H), 6.66-6.41 (m, 1H), 5.01 (td, 7 =15.2, 3.2Hz, 2H) 391 h ₂ nn=\ \—<y N ΆΛζΝ H n\=n o N-|/ X/ 345.3 0.70 δ 8.91 (brd,7=1.1Hz, 1H), 8.83 (d, 7=2.7Hz, 1H), 8.60 (brd,7=1.8Hz, 1H), 8.23 (d, 7=8.6Hz, 1H), 8.14 (brd, 7=1.4 Hz, 1H), 7.96 (br d, 7=8.8 Hz, 1H), 7.85 (s, 1H), 7.37 (brs, 1H), 6.67 - 6.60 (m, 1H), 4.81 (brt , 7=5.9 Hz, 2H), 3.39 - 3.35 (m, 2H)

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392 H ₂ N /А/А A £ J nA^ HN \ 318.2 1.10 5 8.52 (s, 1H), 8.09 (d, 7=8.1 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.65 (brd,7=8.5 Hz, 1H), 7.27 - 6.97 (m, 2H), 6.78 -6.74 (m, 1H), 4.50 (brt, 7=6.7Hz, 2H), 2.58 - 2.53 (m, 2H), 2.24 (quin, 7=6.8Hz, 2H) 393 / \-OH n ^z \ , ^ν Ά_/ kk N О HN \ 349.2 0.86 5 8.51 (s, 1H), 8.06 (d, 7=8.3 Hz, 1H), 7.86 (s, 1H), 7.78 7.65 (m, 1H), 7.61 (brd, 7=7.4 Hz, 1H), 6.83 (br s, 2H), 6.74 (d, 7=1.9 Hz, 1H), 4.86-4.62 (m, 1H), 4.51-4.40 (m, 1H), 3.62-3.53 (m, 1H), 2.20-2.13 (m, 2H ), 2.03 - 1.96 (m, 2H), 1.96-1.85 (m, 2H), 1.49-1.39 (m, 2H) 394 Iz ux ^UM /GA Z^ / ~z. ό I 349.3 1.14 5 8.94 (s, 1H), 8.20 (d, 7=8.3 Hz, 1H), 8.12-8.06 (m, 1H), 7.94-7.88 (m, 1H), 7.87 7.81 (m, 1H), 6.82 (s, 1H), 4.70 (brs, 1H), 4.60–4.52 (m, 1H), 3.60–3.56 (m, 1H), 2.31–2.19 (m, 2H), 1.981.91 (m, 2H), 1.82–1.75 ( m, 2H), 1.73 - 1.63 (m, 2H) 395 nh ₂ Ay™ A hn' j 304.2 0.83 5 13.24-13.05 (m, 1H), 9.01-8.97 (m, 1H), 8.21-8.17 (m, 1H), 8.10 (brs, 1H), 7.93 (brd,7=7.3 Hz, 1H), 7.85 (br s, 1H), 6.82 (brs, 1H), 4.85 4.79 (m, 2H), 3.30 -3.25 (m, 2H) 396 nh ₂ ^oh f £ N—' nJUJ hn' T 295.2 0.96 5 8.71 (s, 1H), 7.96 (d, 7=8.3 Hz, 1H), 7.91 (s, 1H), 7.777.59 (m, 2H), 7.12-6.89 (m, 2H), 6.74 (s, 1H ), 5.10-5.07 (m, 1H), 4.48 (t, 7=5.2 Hz, 2H), 3.93 -3.88 (m, 2H) 397 ^H2N \ A X { p n \—/ a )=\ ^F O nA hn^P 345.2 0.92 5 13.52-12.76 (m, 1H), 8.74 (s, 1H), 7.94 (br d, 7=7.9 Hz, 1H), 7.90 (brs, 1H), 7.81 7.58 (m, 2H), 6.94 - 6.83 (m , 2H), 6.83 - 6.50 (m, 2H), 4.71 (t, 7=5.0 Hz, 2H), 4.37 (t, 7=5.0 Hz, 2H)

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398 BUT HE hn' j 325.1 0.67 5 8.66 (s, IH), 7.96 (d, 7=8.0 Hz, IH), 7.90 (s, IH), 7.69 (br s, IH), 7.63 (br d, 7=7.7 Hz, IH), 6.94 - 6.79 (m, 2H), 6.74 (d, 7=1.9 Hz, IH), 5.16 (brs, IH), 4.93 -4.81 (m, IH), 4.57 (dd, 7=13.8, 3.6 Hz, IH), 4.30 (dd, 7=13.8, 8.3 Hz, IH), 3.98 (brs, IH), 3.51 -3.43 (m, 2H) 399 Ά H ₃ C OH vU hn' j 323.3 1.06 5 13.28 - 12.91 (m, IH), 9.85 - 9.04 (m, 2H), 8.96 (s, IH), 8.11 (brd, 7=8.0 Hz, 2H), 7.89 (brd,7=8.5 Hz, IH), 7.82 (brs, IH), 6.79 (d, 7=1.7 Hz, IH), 4.95 - 4.77 (m, IH), 4.58 (dd, 7=13.3, 6.2 Hz, IH), 4.31 (dd, 7=13.5, 8.0 Hz, IH), 3.41-3.33 (m, 2H), 2.342.24 (m, IH), 0.87 (d, 7=6.9 Hz, 3H) 400 nh ₂ ϊΛρν ЛХн ,νΑΑ d ^СНз 323.1 1.21 5 8.64 (s, IH), 8.48 (brd, 7=8.9Hz, IH), 8.19 (brs, IH), 7.97 (brd,7=7.3Hz, IH), 7.87 (brd,7=2.4Hz, IH) , 6.87 (s, IH), 4.85 - 4.65 (m, 2H), 3.92 (brs, IH), 1.58 (brd,7=7.3Hz, IH), 1.49 (brd, 7=7.3Hz, IH), 0.96 (t, 7=7.2Hz, 3H) 401 nh ₂ ϊ4Πν V>° ^h n-AA hn'Ύ ch ₃ 309.2 0.97 5 8.34 (s, IH), 8.31 (d, 7=8.6 Hz, IH), 8.01 (s, IH), 7.797.71 (m, 2H), 6.82 (d, 7=2.1 Hz, IH), 4.78 - 4.69 (m, IH), 4.58 (dd, 7=14.3, 5.6 Hz, IH), 4.22-4.12 (m, IH), 1.15 (d, 7=6.2 Hz, 3H) 402 NH ₂ ho A ^CF 3 1 N—' /V ^N nXA hn' J 377.2 1.23 5 8.90 (s, IH), 8.22 (d, 7=7.9 Hz, IH), 8.09 (brs, IH), 7.93 (brd,7=8.2 Hz, IH), 7.84 (br s, IH), 6.83 (d , 7=1.5Hz, IH), 4.59 (dd, 7=13.4, 3.1Hz, 1H),4.45 (dd,7=13.7, 8.2Hz, 1H),4.33 (brd,7=3.4Hz, IH), 2.77 - 2.60 (m, IH), 2.47 - 2.35 (m, IH) 403 nh ₂ XjA nAA \ hn' Ύ T on XF 312.9 1.04 5 8.92 (s, IH), 8.27 (brd, 7=1.5 Hz, IH), 7.98 (br d, 7=10.7 Hz, IH), 7.89 (br s, IH), 6.77 (br s, IH), 4.52 (t, 7=4.3Hz, 2H), 3.90 (t, 7=4.3Hz, 2H)

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Example 407 Preparation of 2-(4-α-mino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2methylpropan-1-ol, TFA

Step 1 Ethyl 2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3c]quinolin-2-yl )-2-methylpropanoate.

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (50 mg, 0.150 mmol) in DMF (498 µl) cesium carbonate (146 mg, 0.449 mmol) was added followed by ethyl 2-bromo-2-methylpropanoate (24.14 µl, 0.164 mmol). The suspension was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc (20 ml) and H ₂ O (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 0-10% MeOHCH ₂ Cl ₂ ) to give ethyl 2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H -pyrazol-5-yl)-2Hpyrazolo[4,3-c]quinolin-2-yl)-2-methylpropanoate (50.1 mg, 75% yield) as a white solid. LC-MS m/z 449 [M+H]+; ¹ H NMR (400 MHz, DMSO-A) δ 8.79 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.32 (dd, J=8.0, 1.5 Hz, 1H), 7.16-6.99 (m, 2H), 6.50 (d, J=1.8 Hz, 1H), 5.29 (dd, J=10.0, 2.0 Hz , 1H), 4.13 (q, J=7.1 Hz, 2H), 4.07-3.99 (m, 1H), 3.63-3.54 (m, 1H), 2.49-2.36 (m, 2H), 1.95 (s, 6H), 1.79 (brd, J=12.0 Hz, 1H), 1.62-1.49 (m, 3H), 1.12 (t, J=7.1 Hz, 3H).

Step 2 2-(4-amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methylpropan-1-ol, TFA.

To a suspension of ethyl 2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3s]quinolin-2-yl) -2-methylpropanoate (50.1 mg, 0.112 mmol) in THF (1005 µl) MeOH (112 µl) was added to give a clear colorless solution. The solution was cooled to 0°C and lithium borohydride (2 M solution in THF) (168 μl, 0.335 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 15 minutes, then at room temperature for 1 h. The reaction mixture was diluted with H ₂ O (20 ml) and was extracted with EtOAc (3x10 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo.

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The crude product was mixed with CH2C12 (200 µl) and TFA (200 µl) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH ₂ Cl ₂ (300 μl) and concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter with 0.45 µm Acrodisc nylon membrane) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 µm; 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-minute hold at 0% B, 0-30% B for 20 min, then 4-minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2-(4-amino-7-(1Hpyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2- methylpropan-1-ol, TFA (30.8 mg, 63%). 1Н NMR (500 MHz, DMSO-d ₆ ) δ 13.22 (br s, 1H), 9.60-9.42 (m, 1H), 9.03-8.99 (m, 1H), 8.83-8.61 (m, 1H), 8.22 (d , J=8.2 Hz, 1H), 8.06 (br s, 1H), 7.92 (br d, J=7.9 Hz, 1H), 7.83 (br s, 1H), 6.82 (d, J=2.2 Hz, 1H), 5.32 (br s, 1H), 1.64 (s, 6H); two CH protons are not observed, probably due to the overlap of the water peak. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 323.0 [M+H]+; RT: 0.9 min.

Examples 408-409 were prepared following synthetic procedures similar to those described in Example 407 from the appropriate alkyl chloride or mesylate starting materials. The temperature of the alkylation reaction varied from room temperature to 50°C. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Etc. No. Structure LC/MS [M+H] ⁺ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 408 H ₂ N //χ ² \ γΎγγ nAA On OH N=< ΗΝ γ 362.1 0.72 δ 13.19-12.98 (m, 1H), 9.01-8.83 (m, 1H), 8.92-8.31 (m, 2H), 8.13 (d, 7=8.2 Hz, 1H), 8.02 (brd,7=2.8 Hz, 1H ), 7.91 -7.72 (m, 2H), 6.80 (s, 1H), 6.59 (s, 1H), 5.99 (s, 2H), 5.68 - 5.55 (m, 1H), 4.49 (d, 7=5.6 Hz, 2H) 409 _H2N /X. ^x /~x \ /ZN if OH N AN A/N nA HN A 372.2 0.93 δ 8.60 (s, 1H), 8.45 (d, 7=5.0 Hz, 1H), 8.06 (d, 7=8.0 Hz, 1H), 7.88 (d, 7=1.4 Hz, 1H), 7.71 (br s, 1H ), 7.62 (dd, 7=8.1, 1.2 Hz, 1H), 7.30 (s, 1H), 7.11 (brd, 7=4.7 Hz, 1H), 7.08 - 6.94 (m, 2H), 6.75 (d, 7= 2.2 Hz, 1H), 5.76 (s, 2H), 5.64 -5.36 (m, 1H), 4.53 (s, 2H)

Example 410 Preparation of 3-(4-amino-7(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-3methylbutan-1-ol, TFA

stage 1

ΙΝΠ2 Ar ^N stage 2 LiBH ₄ MeOH, THF from 0°C to rt TFA CH ₂ CI ₂ , rt; Et ₃ N, MeOH CH2CI2J rt Ύ osn ^s ^y ^osn s s ₃ 0 Ϊ L / ^s ZhsnR cs co ' ^τ ζ AA Y ^/82^^3 \ l| DMF, 50 °C ΝχΧΑ M N ^h 2 OH sn? ^НЗ n^A^Z hn' j

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Step 1. Methyl 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3c]quinolin-2-yl )-3-methylbutanoate.

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-4amine (30 mg, 0.090 mmol) in DMF (299 µl) cesium carbonate (88 mg, 0.269 mmol) was added followed by methyl 3-methylbut-2-enoate (12.90 µl, 0.099 mmol). The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was stirred at 50° C. for 2 hours. Additional methyl 3-methylbut-2-enoate (25.8 μl, 0.198 mmol) was added. The reaction mixture was stirred at 50° C. for 22 hours. Additional methyl 3-methylbut-2-enoate (50 μl) was added. The reaction mixture was stirred at room temperature for 16 hours. Additional methyl 3-methylbut-2-enoate (50 μl) was added. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with EtOAc (20 ml) and H ₂ O (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (12 g silica gel; linear gradient 010% MeOH-CH ₂ Cl ₂ ) to give methyl-3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)- 1H-pyrazol-5-yl)2H-pyrazolo[4,3-c]quinolin-2-yl)-3-methylbutanoate as a mixture with unreacted starting compound (20 mg). This product was used without further purification.

Step 2 3-(4-Amino-7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-3-methylbutan-1-ol, TFA.

The product obtained in the previous step was suspended in THF (401 µl) and then MeOH (44.6 µl) was added. The mixture was cooled to 0° C. and lithium borohydride (2 M solution in THF) (66.9 μl, 0.134 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 h. Additional LiBH ₄ (67 μl) was added. The reaction mixture was stirred at room temperature for 30 minutes. An additional amount of LiBH ₄ (134 μl) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (3x10 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na2SO4, filtered and concentrated in vacuo.

The crude product was mixed with CH ₂ Cl ₂ (150 μl) and TFA (150 μl) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH ₂ Cl ₂ (300 μl) and concentrated in vacuo.

The crude product was mixed with CH ₂ Cl ₂ (150 μl) and MeOH (150 μl) and triethylamine (31.1 μl, 0.223 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo. The crude product was dissolved in CH ₂ Cl ₂ (300 μl) and concentrated in vacuo. The crude product was dissolved in DMF (2 ml), filtered (syringe filter with 0.45 µm Acrodisc nylon membrane) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 µm; 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 min hold at 1% B, 1-41% B for 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 3-(4-amino-7-(1H-pyrazol-3-yl)-2Hpyrazolo[4,3-c]quinolin-2-yl)-3- methylbutan-1-ol TFA (10.2 mg, 50%). 1Н NMR (500 MHz, DMSO-d ₆ ) δ 13.22-13.01 (m, 1H), 9.59-9.35 (m, 1H), 9.04 (s, 1H), 8.91-8.72 (m, 1H), 8.21 (d, J=8.3 Hz, 1H), 8.10 (br s, 1H), 7.92 (br d, J=7.9 Hz, 1H), 7.85 (br s, 1H), 6.82 (d, J=1.9 Hz, 1H), 4.58 (br s, 1H), 3.29 (br t, J=6.8 Hz, 2H), 2.19 (t, J=6.9 Hz, 2H), 1.72 (s, 6H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1x50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 337.2 [M+H]+; RT: 1.1 min.

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Example 411 Preparation of 2-[(morpholin-4-yl)methyl]-7-(III-pyrazol-5-yl)-III-pyrrolo[3,2-c]quinoline4-amine

Step 1. 7-bromo-N-(4-methoxybenzyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)-prop-1-yn-1yl)quinolin-4-amine.

Triethylamine (5.81 ml, 41.7 mmol). The mixture was purged with N ₂ for 15 min, then bis(triphenylphosphine)palladium(II) dichloride (0.146 g, 0.208 mmol) and copper(I) iodide (0.099 g, 0.521 mmol) were added. The mixture was purged with N2 for 2 min, then 2(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (1.753 g, 12.51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with EtOAc (300 ml), washed with aqueous LiCl solution (3x200 ml) and saturated aqueous NaCl solution (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo . The crude product was mixed with Et ₂ O (50 ml), the solids were collected by vacuum filtration and washed with Et ₂ O (4x10 ml). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (40 g silica gel; linear gradient 0-100% EtOAc hexanes). The chromatography product was combined with solids after filtration to give 7-bromo-K[-(4-methoxybenzyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1- yl)quinoline-4-amine (4.62 g, 92%) as a yellow solid. LC-MS m/z 481/483 [M+H]+; 1Н NMR (400 MHz, DMSOd ₆ ) δ 8.36-8.30 (m, 2H), 8.00-7.95 (m, 2H), 7.66 (dd, J=9.0, 2.1 Hz, 1H), 7.26 (d, J=8.7 Hz , 2Н), 6.89-6.84 (m, 2Н), 5.09 (d, J=6.7 Hz, 2Н), 4.74-4.71 (m, 1H), 4.48-4.42 (m, 1H), 4.39-4.32 (m, 1H ), 3.78-3.71 (m, 1H), 3.70 (s, 3H), 3.50-3.41 (m, 1H), 1.76-1.57 (m, 2H), 1.54-1.42 (m, 4H).

Step 2. 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2c]quinoline.

7-Bromo-N-(4-methoxybenzyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)quinolin4-amine mixture (3.540 g, 7 .35 mmol) and potassium tert-butoxide (1.650 g, 14.71 mmol) in THF (36.8 ml) were stirred

- 162 042018 at room temperature for 24 hours The reaction was quenched by adding a saturated aqueous solution of NH ₄ Cl (200 ml) and was extracted with EtOAc (2x200 ml). The combined organic layers were washed with saturated aqueous NaCl (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (80 g silica gel; linear gradient 0100% EtOAc-hexanes) to give 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2yl)oxy)methyl) -1H-pyrrolo[3,2-c]quinoline (2.87 g, 81%) as an off-white solid. LCMS m/z 481/483 [M+H]+; ¹ H NMR (400 MHz, DMSO-k) δ 9.16 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.57 (dd, J=9.0 , 2.1 Hz, 1H), 7.00 (s, 1H), 6.90-6.86 (m, 2H), 6.85-6.81 (m, 2H), 5.87 (s, 2H), 4.90 (d, J=12.8 Hz, 1H) , 4.73-4.67 (m, 2H), 3.74 (ddd, J=11.2, 8.4, 2.3 Hz, 1H), 3.66 (s, 3H), 3.50-3.44 (m, 1H), 1.581.33 (m, 5H) , 1.28-1.19 (m, 1H).

Step 3. 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2c]quinoline-5-oxide.

To a solution of 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1Hpyrrolo[3,2-c]quinoline (2.87 g, 5 .96 mmol) in CH ₂ Cl ₂ (29.8 ml) was added portionwise 3-chloroperoxybenzoic acid (<77%) (1.737 g, 7.75 mmol). The clear orange solution was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 (200 ml), washed with a 1:1 mixture of 10% w/w, aqueous Na ₂ S ₂ O ₃ and saturated aqueous NaHCO ₃ (2x200 ml) and then H2O (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ). The mixed fractions were repurified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ). Fractions containing product from both columns were combined to give 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3.2c ]quinoline-5-oxide (2.591 g, 87%) as an orange foam. LC-MS m/z 497/499 [M+H]+; 1Н NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.90 (d, J=2.1 Hz, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.76 (dd, J=9.0, 2.2 Hz, 1H), 6.92-6.88 (m, 3H), 6.86-6.82 (m, 2H), 5.85 (s, 2H), 4.88 (d, J=12.8 Hz, 1H), 4.71-4.66 (m, 2H ), 3.76-3.69 (m, 1H), 3.66 (s, 3H), 3.50-3.43 (m, 1H), 1.58-1.33 (m, 5H), 1.28-1.20 (m, 1H).

Stage 4. 7-bromo-N,1-bis(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)-oxy)methyl)-1Hpyrrolo[3,2-c]quinoline-4 -amine.

To a solution of 7-bromo-1-(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)-methyl)-1Hpyrrolo[3,2-c]quinoline 5-oxide (2.590 g , 5.21 mmol) in CH ₂ Cl ₂ (26.0 ml) were added N,Ndiisopropylethylamine (2.72 ml, 15.62 mmol), 4-methoxybenzylamine (0.816 ml, 6.25 mmol) and PyBroP (2. 91 g, 6.25 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with CH ₂ Cl ₂ (200 ml), washed with H ₂ O (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (80 g silica gel; linear gradient 0-100% EtOAc-hexanes) to give 7-bromo-M,1-bis(4-methoxybenzyl)-2(((tetrahydro-2H-pyran-2- yl)oxy)-methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (2.414 g, 75%) as a yellow solid. LC-MS m/z 616/618 [M+H]+; 1Н NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (t, J=6.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.1 Hz, 1H), 7.37 ( d, J=8.7 Hz, 2H), 7.10 (dd, J=8.8, 2.2 Hz, 1H), 7.06 (s, 1H), 6.90-6.86 (m, 4H), 6.85-6.82 (m, 2H), 5.75 (s, 2H), 4.80 (d, J=12.8Hz, 1H), 4.72 (d, J=6.0Hz, 2H), 4.67 (t, J=3.4Hz, 1H), 4.61 (d, J=12.8Hz , 1H), 3.72 (s, 3H), 3.76-3.70 (m, 1H), 3.67 (s, 3H), 3.49-3.42 (m, 1H), 1.601.33 (m, 5H), 1.29-1.21 (m , 1H).

Step 5. N,1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)-2(((tetrahydro-2H-pyran -2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine.

A mixture of 7-bromo-N,1-bis(4-methoxybenzyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1Hpyrrolo[3,2-c]quinoline-4-amine ( 2.414 g, 3.92 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.416 g, 5.09 mmol) and tribasic potassium phosphate (2.493 g, 11.75 mmol) were evacuated and refilled with N2, then it was mixed with 1,4-dioxane (16.31 ml) and H2O (3.26 ml ). The resulting mixture was bubbled with N2 for 15 min, then chloro(2dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] was added. palladium(11) (0.062 g, 0.078 mmol). The reaction mixture was stirred at 100°C for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (200 ml), washed with H ₂ O (3x200 ml) and saturated aqueous NaCl (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (80 g silica gel; linear gradient 0100% EtOAc-hexanes) to give N,1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1Hpyrazole -5-yl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (2.644 g, 98%) as orange foam. LC-MS m/z 688 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (d, J=8.6 Hz, 1H), 7.78-7.72 (m, 2H), 7.54 (d, J=1.8 Hz, 1H), 7.40 (d, J =8.7 Hz, 2H), 7.12 (dd, J=8.5, 1.9 Hz, 1H), 7.06 (s, 1H), 6.93-6.89 (m, 2H), 6.88-6.81 (m, 4H), 6.47 (d, J=1.8 Hz, 1H), 5.79 (s, 2H), 5.20 (br d, J=9.8 Hz, 1H), 4.83 (d, J=12.5 Hz, 1H), 4.79-4.72 (m, 1H), 4.71 -4.66 (m, 2H), 4.66-4.60 (m, 1H), 4.07-3.99 (m, 1H), 3.70 (s, 3H), 3.77-3.69 (m, 1H), 3.66 (s, 3H), 3.55 -3.44 (m, 2H), 2.45-2.34 (m, 1H), 1.97-1.89 (m, 1H), 1.74 (br d, J=12.2 Hz, 1H), 1.61-1.34 (m, 8H), 1.30- 1.21(m, 1H).

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Step 6. (1-(4-Methoxybenzyl)-4-((4-methoxybenzyl)amino)-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2c]quinolin-2-yl )methanol.

To a suspension of N, 1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2(((tetrahydro-2H-pyran-2 -yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (500 mg, 0.727 mmol) in MeOH (7269 μl) was added 4 M hydrochloric acid in 1,4-dioxane (363 μl , 1.454 mmol). The mixture was sonicated until it turned into a clear yellow solution. The reaction mixture was stirred at room temperature for 45 minutes, whereupon a suspension formed. The reaction mixture was added to Et ₂ O (70 ml), the solids were collected by vacuum filtration and washed with Et ₂ O (2x4 ml). The solids were mixed with 20% MeOH-CH ₂ Cl ₂ (200 ml) and saturated aqueous NaHCO ₃ (200 ml). The layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1-(4-methoxybenzyl)-4-((4methoxybenzyl)amino)-7-(1H-pyrazol-3-yl)- 1H-pyrrolo[3,2-c]quinolin-2-yl)methanol (361 mg, 96%) as a white solid. LC-MS m/z 520 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 13.26-12.80 (m, 1H), 7.95 (d, J=1.9 Hz, 1H), 7.87-7.82 (m, 1H), 7.75 (s, 1H), 7.70 -7.53 (m, 1H), 7.51-7.43 (m, 1H), 7.41-7.32 (m, 2H), 6.97-6.91 (m, 3H), 6.90-6.82 (m, 4H), 6.76-6.67 (m, 1H), 5.79 (br s, 2H), 5.40-5.33 (m, 1H), 4.80-4.71 (m, 2H), 4.63-4.55 (m, 2H), 3.70 (s, 3H), 3.66 (s, 3H ).

Step 7 1-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2c]quinoline-2-carbaldehyde.

To a suspension of (1-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-7-(1H-pyrazol-3-yl)-1Hpyrrolo[3,2-c]quinolin-2-yl)methanol ( 0.361 g, 0.695 mmol) in CH ₂ Cl ₂ (19.85 ml) was added Dess-Martin periodinan (0.589 g, 1.390 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The reaction was quenched by adding a mixture of 10% aq. Na ₂ S ₂ O ₃ (10 ml) and saturated aqueous NaHCO ₃ (10 ml) and stirred vigorously for 30 min, then extracted with 10% MeOH-CH ₂ Cl ₂ (2x20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by flash chromatography (40 g silica gel; linear gradient 0-10% MeOH-CH ₂ Cl ₂ ) to give 1-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-7-(1Hpyrazole- 3-yl)-1H-pyrrolo[3,2-c]quinoline-2-carbaldehyde, mixed with a small amount of the corresponding product without one of the 4-methoxybenzylamino groups (309 mg, 86%) as a yellow solid, which was used without additional cleaning. LC-MS m/z 518 [M+H] ⁺ .

Steps 8 and 9 2-(morpholinomethyl)-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine, 2 AcOH.

To a suspension of 1-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2c]quinoline-2-carbaldehyde (47 .7 mg, 0.092 mmol) in DCE (461 μl) at room temperature were added morpholine (11.92 μl, 0.138 mmol) and trimethyl orthoformate (81 μl, 0.737 mmol). The reaction mixture was stirred at room temperature for 1 h, then sodium triacetoxyborohydride (39.1 mg, 0.184 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Additional sodium triacetoxyborohydride (20 mg, 0.094 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (4 ml) and extracted with CH ₂ Cl ₂ (2x4 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo.

The crude product was dissolved in TFA (415 µl) and TfOH (46 µl) was added. The reaction mixture was sealed and stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature and added dropwise to Et ₂ O (15 ml). The resulting solids were collected by vacuum filtration. This product was purified by preparative HPLC (three 1 ml injections) (column: Waters XBridge 19x100 mm; linear gradient 10-90% VA over 10 min; solvent A=5% MeCN-H ₂ O with 10 mM NH ₄ OAc; solvent B=95% MeCN-H ₂ O with 10 mM NH ₄ OAc, flow rate: 30 ml/min, detector wavelength: 220 nm). Fractions containing the product were frozen at -78°C and lyophilized to obtain 2-(morpholinemethyl)-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine, 2 AcOH (21.6 mg, 50%) as a white solid. 1Н NMR (400 MHz, DMSO-d ₆ ) δ 12.05 -11.95 (m, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.68 (br s, 1H), 7.59 (br d, J=8.6 Hz, 1H), 6.73 (d, J=2.0 Hz, 1H), 6.64 (s, 1H), 6.52 (s, 2H), 3.63 (s, 2H), 3.62 -3.59 (m, 4H), 2.44 (br s, 4H), 1.88 (s, 6H). Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). m/z 349.2 [M+H]+; RT: 0.45 min.

Compounds of Examples 412-422 were prepared according to synthetic procedures similar to those described for Examples 150, 151 and 411 from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

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Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 412 H ₂ N 0 M N=( hn/J 377.0 0.84 δ 8.31 (brt, 7=5.6 Hz, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.95 (s, 1H), 7.77 - 7.62 (m, 2H), 6.76 (s, 1H), 6.64 ( s, 1H), 4.55 - 4.37 (m, 2H), 4.29 (dd, 7=8.1, 5.6 Hz, 1H), 3.98 3.88 (m, 1H), 3.79 (q, 7=6.9 Hz, 1H), 2.17 ( brdd, 7=12.2, 7.6Hz, 1H), 1.84 (quin, 7=6.7Hz, 2H) 413 h ₂ n 0 z\ °xX 0 N=z HN^ 391.2 1.05 5 8.12-8.00 (m, 2H), 7.93 (s, 1H), 7.70 (br s, 1H), 7.65 (br d, 7=7.9 Hz, 1H), 6.74 (s, 1H), 6.61 (s, 1H ),4.47 (brt, 7=6.0 Hz, 2H), 3.97 (br d, 7=10.7 Hz, 1H), 3.80 (brd, 7=11.3 Hz, 1H), 1.93 (brs, 1H), 1.85 - 1.74 ( m, 1H), 1.60 - 1.30 (m, 4H) 414 ^N L /XH ^N _v Vnh /\ ⁰ 0 N=Z ^HN \^ 391.2 0.86 5 8.22 (brd, 7=8.5 Hz, 1H), 8.13 (brs, 1H), 8.00-7.75 (m, 4H), 6.84 (br s, 2H), 4.18 (dd, 7=8.2, 5.2 Hz, 1H) , 3.893.78 (m, 1H), 3.77 -3.68 (m, 1H), 3.62 (brd, 7=7.0 Hz, 1H), 3.47 (dt, 7=13.0, 6.8 Hz, 1H), 2.96 (brt, 7 =7.0 Hz, 2H), 2.17-2.00 (m, 2H), 1.85 - 1.60 (m, 4H) 415 ^N L H o^x ^N , V NH /\ ⁰ 0 N=/ HN.) 405.1 0.99 5 8.28 - 8.17 (m, 1H), 8.12 (brs, 1H), 7.98 - 7.89 (m, 2H), 7.86 - 7.75 (m, 2H), 6.84 (br s, 2H), 3.92 (br d, 7= 10.4 Hz, 1H), 3.75 - 3.64 (m, 1H), 3.50 - 3.33 (m, 2H), 2.96 (br t, 7=7.0 Hz, 2H), 1.87-1.70 (m, 2H), 1.57 - 1.36 ( m, 4H), 1.31 - 1.16 (m, 1H)

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416 n Ό Η ₂ Ν Χ'ΑνΗ 0 Ο Ν=< ΗΝ^ 416.2 1.62 δ 9.09 (brt, 7=6.0 Hz, 1H), 8.75 - 8.62 (m, 1H), 8.22 (br d,7=8.5 Hz, 1H), 8.13 (brs, 1H), 7.99 - 7.90 (m, 1H) , 7.86 -7.73 (m, 2H), 7.53 (brt, 7=5.8Hz, 1H), 6.93 -6.73 (m, 2H), 3.72 (brd,7=6.7Hz, 2H), 3.10 (brt, 7=7.0 Hz, 2H) 417 ⁿ ϊΤ Η ₂ Ν Ν^Α—ΝΗ 0 Ο Ν=< ΗΝ^ 416.1 1.62 Ή NMR (500 MHz, DMSOd ₆ ) δ 8.91 (brt, 7=5.3 Hz, 1H), 8.62 (brs, 1H), 8.13 (br dd, 7=8.5, 4.6 Hz, 1H), 8.07 (brd, 7= 8.2 Hz, 1H), 7.977.85 (m, 2H), 7.70 (br s, 1H), 7.65 (br d, 7=7.6 Hz, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 3.71 (brd, 7=5.8Hz, 2H), 3.07 (brt,7=7.0Hz, 2H) 418 0 Η ₂ Ν JL ² x/ud^X h /^νη ^η n^A _f Ν=/ ΗΝ^Ζ 402.0 1.21 δ 9.42 (t, 7=6.1 Hz, 1H), 8.70 (brs, 2H), 8.25 (brd,7=8.2 Hz, 1H), 8.20 - 8.04 (m, 2H), 8.03 - 7.88 (m, 2H), 7.85 (br s, 1H), 6.98 (s, 1H), 6.83 (d, 7=2.0 Hz, 1H), 4.71 (brd, 7=6.0 Hz, 2H) 419 Η ₂ Ν /\YUSN ₃ ² \ /χ Ν ⁴ ^ ³ UAUN ^η Ν=< ΗΝ^Ζ 337.2 0.88 δ 8.24 (d, 7=8.5 Hz, 1H), 8.18 (brs, 1H), 8.00 (brd,7=7.9 Hz, 1H), 7.85 (brs, 1H), 7.27 (s, 1H), 6.86 (d, 7=2.1Hz, 1H), 4.43(s, 2H), 3.63(brt, 7=4.9Hz, 2H), 3.33(s, 3H), 3.22(brt, 7=4.9Hz, 2H) 420 η ₂ ν N^yX^^CH ₃ 0 Ν=Λ 306.9 0.83 δ 8.25 (d, 7=8.2 Hz, 1H), 8.19 (brs, 1H), 8.00 (brd, 7=8.5 Hz, 1H), 7.87 (br s, 1H), 7.26 (s, 1H), 6.85 (d , 7=1.8 Hz, 1H), 4.41 (s, 2H), 3.08 (q,7=7.5 Hz, 2H), 1.26 (t, 7=7.3 Hz, 3H) 421 2, ζ ΞΕ 349.3 0.83 δ 8.24 (d, 7=8.2Hz, 1H), 8.18 (brs, 1H), 8.00 (brd,7=8.5Hz, 1H), 7.85 (brd,7=2.1Hz, 1H), 7.25 (s, 1H) , 6.85 (d, 7=2.1 Hz, 1H), 4.39 (brs, 2H), 4.01 -3.86 (m, 2H), 3.85 -3.78 (m, 1H), 3.74-3.64 (m, 1H), 2.29 (m 1H),2.13 1.96 (m, 1H) 422 ΞΕ Z ^ζ 349.1 0.84 6 8.24 (d, 7=8.5 Hz, 1H), 8.17 (s, 1H), 8.00 (d, 7=8.5 Hz, 1H), 7.85 (s, 1H), 7.27 (s, 1H), 6.86 (d, 7=2.1 Hz, 1H), 4.42 (s, 2H), 4.00 -3.90 (m, 3H), 3.86 -3.79 (m, 1H), 3.74 -3.64 (m, 1H), 2.31 (m Hz, 1H), 2.06 (mlH)

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Example 423 Preparation of 2,3-dimethyl-7-(III-pyrazol-3-yl)-III-pyrrolo[3,2-c]quinoline-4-amine

Stage 1. 3-bromo-N, 1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)-2(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)-III-pyrrolo[3,2-c]quinoline-4-amine.

To a solution of N, 1 -bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2(((tetrahydro-2H-pyran-2 -yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (510 mg, 0.741 mmol) in DMF (4943 μl) was added N-bromosuccinimide (139 mg, 0.779 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with EtOAc (100 ml), washed with H ₂ O (2x100 ml) and saturated aqueous NaCl (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (24 g silica gel; linear gradient 0-100% EtOAc-hexanes) to give 3-bromo-N,1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2Hpyran-2- yl)-1H-pyrazol-5-yl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4amine (506 mg, 89 %) as a yellow foam. LC-MS m/z 766/768 [M+H]+; 1H NMR (400 MHz, DMSO-d ₆ ) δ 7.96 (d, J=8.6 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.45- 7.41 (m, 2H), 7.18 (dd, J=8.6, 1.9 Hz, 1H), 6.98-6.92 (m, 3H), 6.90 - 6.83 (m, 4H), 6.50 (d, J=1.8 Hz, 1H) , 5.87 (s, 2H), 5.20 (br d, J=9.7 Hz, 1H), 4.88 (dd, J=12.8, 1.8 Hz, 1H), 4.85-4.79 (m, 1H), 4.79-4.73 (m, 1H), 4.73-4.66 (m, 2H), 4.06-3.99 (m, 1H), 3.793.71 (m, 1H), 3.71 (s, 3H), 3.66 (s, 3H), 3.55-3.43 (m, 2H), 2.46-2.34 (m, 1H), 1.97-1.88 (m, 1H), 1.75 (br d, J=12.5 Hz, 1H), 1.62-1.32 (m, 8H), 1.25-1.18 (m, 1H ).

Step 2. N,1-bis(4-methoxybenzyl)-3-methyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine.

A mixture of 3-bromo-N,1-bis(4-methoxybenzyl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2(((tetrahydro-2H- pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (268 mg, 0.350 mmol), methylboronic acid (27.2 mg, 0.454 mmol) and tribasic potassium phosphate ( 223 mg, 1.049 mmol) was evacuated and refilled with N2, then it was mixed with 1,4-dioxane (1942 µl) and H2O (388 µl). The mixture was purged with N2 for 25 min, then chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,T-biphenyl)[2-(2'-amino-1,T-biphenyl)]palladium( P) (13.75 mg, 0.017 mmol). The reaction mixture was sealed and stirred at 100°C for 30 min. Additional methylboronic acid (27.2 mg, 0.454 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'triisopropyl-1,G-biphenyl)-[2-(2'-amino-1,G -biphenyl)]palladium(II) (13.75 mg, 0.017 mmol). The reaction mixture was stirred at 100°C for 30 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with H ₂ O (100 ml) and saturated aqueous NaCl (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (40 g RediSep Gold silica gel; linear gradient 0-75% EtOAcCH ₂ Cl ₂ ) to give N,1-bis(4-methoxybenzyl)-3-methyl-7-(1-(tetrahydro-2H -pyran-2-yl)-1H-pyrazol5-yl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (173 mg, 71%) as a yellow foam. LC-MS m/z 702 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (d, J=8.7 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 7.11 (dd, J=8.5, 1.8 Hz, 1H), 6.93-6.87 (m, 2H), 6.87-6.81 (m, 4H), 6.73 (t, J=6.0 Hz, 1H), 6.47 (d, J=1.8 Hz, 1H), 5.79 (s, 2H), 5.19 (br d, J=9.9 Hz, 1H), 4.81-167 042018

4.60 (m, 5H), 4.06-3.99 (m, 1H), 3.79-3.71 (m, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 3.53-3.44 (m, 2H), 2.60 ( s, 3H), 2.45-2.35 (m, 1H), 1.98-1.88 (m, 1H), 1.74 (br d, J=11.9 Hz, 1H), 1.64-1.34 (m, 8H), 1.27-1.20 (m , 1H)

step 3 2-yl)methanol.

To a suspension of N, 1-bis(4-methoxybenzyl)-3-methyl-7-(1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-5-yl)2-(((tetrahydro- 2H-pyran-2-yl)oxy)methyl)-1H-pyrrolo[3,2-c]quinoline-4-amine (172 mg, 0.245 mmol) in MeOH (2451 μl) was added 4 M hydrochloric acid in 1.4 -dioxane (123 μl, 0.490 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to Et ₂ O (20 ml), the solids were collected by vacuum filtration and washed with Et ₂ O (2x3 ml). The solids were mixed with 10% MeOH-CH ₂ Cl ₂ (100 ml) and saturated aqueous NaHCO3 (100 ml). The layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give (1-(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-3-methyl-7-(1H-pyrazole3 -yl)-1H-pyrrolo[3,2-c]quinolin-2-yl)methanol (104 mg, 80%) as a white solid. LC-MS m/z 534 [M+H]+; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.25-12.80 (m, 1H), 7.95-7.92 (m, 1H), 7.88-7.71 (m, 1H), 7.51-7.31 (m, 3H), 6.94 -6.89 (m, 4H), 6.88-6.82 (m, 3H), 6.75-6.68 (m, 1H), 6.58-6.46 (m, 1H), 5.81 (br s, 2H), 5.19-5.12 (m, 1H ), 4.82-4.75 (m, 2H), 4.57-4.53 (m, 2H), 3.71 (s, 3H), 3.67 (s, 3H), 2.57 (s, 3H).

Step 4 2,3-dimethyl-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine

To a solution of (1 -(4-methoxybenzyl)-4-((4-methoxybenzyl)amino)-3-methyl-7-(1H-pyrazol-3 -yl)-1Hpyrrolo[3,2-c]quinoline-2 -yl)methanol (24 mg, 0.045 mmol) in TFA (202 µl) were added triethylsilane (35.9 µl, 0.225 mmol) and TfOH (22.49 µl). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo. The crude material was dissolved in MeOH (300 μl) and concentrated in vacuo. The crude material was dissolved in DMF (2 ml), filtered (syringe filter) and purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with ammonium acetate; mobile phase B: 95:5 acetonitrile:water with ammonium acetate; gradient: 0 minute hold at 2% B, 2-42% B for 20 minutes, then 0 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2,3-dimethyl-7-(1H-pyrazol-3-yl)-1H-pyrrolo[3,2-c]quinoline-4-amine (5, 8 mg, 47%). 1H NMR (500 MHz, DMSO-d ₆ ) δ 11.84 (br s, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.69 (br s, 1H), 7.63 (br d, J=8.3 Hz, 1H), 6.73 (d, J=1.7 Hz, 1H), 6.49-6.36 (m, 2H), 2.36 (s, 3H), 2.34 (s, 3H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 278.2 [M+H]+; RT: 1.12 min.

Compounds of Examples 424-456 were prepared according to synthetic procedures similar to those described for Examples 150, 151, 209, 253, or 286 from the appropriate starting materials. Analytical LC/MS conditions.

A: column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

B: column: CORTECS C18, 2.1x50 mm, particles 2.7 µm; mobile phase A: water with 0.09% FA; mobile phase B: acetonitrile with 0.1% FA; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

C: column: Shim-pack XR-ODS, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 95% B over 2 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

D: column: Kinetex XB-C18, 2.1x30 mm, particles 1.7 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 100% B over 1.2 min, then hold 0.6 min at 100% B; flow rate: 1 ml/min; detection: MS and UV.

E: column: Kinetex EVO C18, 3.0x50 mm, particles 2.2 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 95% B over 2 min, then hold 0.6 min at 95% B; flow rate: 1 ml min; detection: MS and UV.

F: Column: PoroShell HPH C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 5 mM ammonium bicarbonate; mobile phase B: acetonitrile; temperature: 40°C; gradient: 5 to 60% B in 3 min, then to 95% in 0.2 min, then hold 1.0 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

G: column: Xbridge BH Shield RP18, 2.1x50 mm, particles 2.5 µm; mobile phase A: 0.1 NH3.H2O; mobile phase B: acetonitrile; temperature: 40°C; gradient: 10 to 50% B in 2.2 min, then to 95% in 0.6 min, then hold 0.7 min at 95% B; flow rate: 1 ml/min; detection: MS and UV.

H: column: Ascentis Express C18, 3.0x50 mm, particles 2.7 µm; mobile phase A: water with 0.05%

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TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 5 to 95% B over 2.0 min, then hold 0.7 min at 95% B; flow rate: 1.5 ml/min; detection: MS and UV.

I: column: Titan C18, 2.1x50 mm, particles 1.9 µm; mobile phase A: water with 0.05% TFA; mobile phase B: acetonitrile with 0.05% TFA; temperature: 40°C; gradient: 10 to 95% over 2.0 min, then hold 0.65 min at 95% B; flow rate: 0.7 ml/min; detection: MS and UV.

J: column: Shim-pack XR-ODS, 3.0x50 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 to 30% in 2.5 min, then to 95% B in 0.7 min, then hold 1.0 min at 95% B; flow rate: 1.2 ml/min; detection: MS and UV.

Etc. No. Structure LC/MS [Μ+Η] ⁺ RT (min) Ή NMR, 400 MHz, Methanol-A unless otherwise noted 424 H ₂ N Η,Γ ϊ ο ν-ν 350.0 1.16/Α 5 8.72 (s, 1Н), 8.39 - 8.35 (br, 2Н), 8.04 (t, J= 1.6 Hz, 1Н), 7.91-7.89 (m, 1Н), 7.81 (d, J= 1.8 Hz, 1Н), 6.61-6.60 (t, 1H), 4.60 (t, 7= 8.4 Hz, 1H), 4.50 - 4.42 (t, 2H), 1.88 (s, ZN), 1.28 (d, 7=6.5 Hz, ZN)

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425 H ₂ N CH _{3 o} jj h ^CH 3 o nn Ta 364.4 0.95/B δ 8.72 - 8.71 (m, 1H), 8.38 (d, J= 2.7 Hz, 1H), 8.35 (t, J = 8.6 Hz, 1H), 8.02 (d, 7=8.4 Hz, 1H), 7.90 (d, 7= 7.5Hz, 1H), 7.80 (d,7= 1.7Hz, 1H), 6.60 (m, 1H), 4.53 (d, 7=6.3Hz, 2H), 3.93 - 3.88 (m, 1H), 2.28- 2.22 (m, 1H), 2.152.06 (m, 1H), 1.98 (s, 3H), 1.21 (d,7=6.7Hz, 3H) 426 h ₂ n ch ₃ N NH ₂ o Nn that 322.1 1.1/1 δ 8.86 (s, 1H), 8.41 - 8.35 (m, 2H), 8.06 - 8.04 (m, 1H), 7.98-7.92 (m, 1H), 7.81 (d, 7= 1.8 Hz, 1H), 6.62-6.61 (m, 1H), 4.87 - 4.62 (m, 2H), 3.49-3.42 (m, 1H), 2.5O2.41 (m, 1H), 2.33-2.24 (m, 1H), 1.43 (d, 7= 6.6 Hz, 3H) 427 nh ₂ ΪΓΤν nAA \ ph HN T /~CH3 H ₃ c 337.2 0.92/C 6 8.49-8.46 (m, 2H), 8.14 (s, 1H), 8.07-8.05 (m, 1H), 7.797.78 (d,7= 2.4 Hz, 1H), 6.87-6.86 (d, 7= 2.4 Hz, 1H), 4.99-4.95 (m, 2H), 2.172.13 (m, 2H), 1.36 (s, 3H) 428 nh ₂ Ϊ IpN ГТ t PH ,ν^ΑΑΑ hn' Ύ ch ₃ 309.2 1.15/C 6 8.58-8.55 (m, 2H), 8.13 (s, 1H), 8.09-8.06 (m, 1H), 7.817.80 (d, 7= 2.4 Hz, 1H), 6.89-6.88 (d, 7=2.4 Hz, 1H), 4.89-4.75 (m, 2H), 4.424.37 (m, 1H), 1.39-1.38 (d, 7 = 6.4 Hz, 3H) 429 nh ₂ HI M / ^CHz Νχ / Α l 0 HN Ύ HN-f CH ₃ 350.3 0.54/D 612.96 (s, 1H), 8.49 (s, 1H), 8.44 (d, 7 = 8.5 Hz, 1H), 8.28 (s, 1H), 8.02 (d, 7= 8.5 Hz, 2H), 7.84 (s, 2H ), 7.00 (s, 1H), 6.93 (s, 1H), 6.84 (s, 1H), 4.85-4.76 (m, 1H), 4.344.58 (m, 7= 14.3.7.8 Hz, 1H), 4.36 ( s, 1H), 1.77 (s, 3H), 1.05 (d, 7= 6.7 Hz, 3H) 430 nh ₂ TjO N^zAA λ HN JN^ m A F 370.2 1.23/E 6 8.61 (s, 1H), 8.43-8.40 (d,7 = 8.6 Hz, 1H), 8.15 (s, 1H), 8.10-8.04 (m, 1H), 7.80-7.79 (d, 7=2.4 Hz, 1H), 6.886.87 (d, 7= 2.4 Hz, 1H), 5.01-4.98 (t,7=5.9 Hz, 2H), 4.99-4.88 (t, 7=5.9 Hz, 4H), 3.47- 3.43 (m, 2H)

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431 H ₂ N ch ₃ N >N h G G to-/ ^{n s} 0 Q nn 396.0 1.34/Α δ 8.74 (s, 1H), 8.39 - 8.34 (m, 2H), 8.05 (d, 7=2.1 Hz, 1H), 7.92-7.90 (m, 1H), 7.81 (d, 7= 1.8 Hz, 1H), 6.61-6.60 (m, 1H), 4.69 - 4.65 (m, 1H), 4.59-4.47 (m, 2H), 1.45 (d, 7= 21.7 Hz, 3H), 1.40-1.34 (m, 6H) 432 nh ₂ iAPn iil^ ^N v / ^0H /\ ^HN ' Ύ H ₃ C CH ₃ 323.2 1.21/S 6 8.75-8.73 (d, 7=8.7 Hz, 1H), 8.56 (s, 1H), 8.12 (s, 1H), 8.03-8.01 (m, 1H), 7.817.80 (d, 7= 2.4 Hz , 1H), 6.89-6.88 (d,7=2.4 Hz, 1H), 4.89-4.85 (m, 2H), 1.31 (s, 6H) 433 C ⁿ M Y\ / t ) ( o O 'ζ 1 ζ -'I 350.4 1.73/F 6 8.64-8.55 (m, 2H), 8.18 (d, 7= 8.5 Hz, 1H), 7.94 (s, 1H), 7.84 - 7.69 (m, 2H), 7.51 (s, 1H), 6.59 (t, 7 = 2.1 Hz, 1H), 4.51-4.37 (m, 1H), 4.31-4.01 (m, 1H), 3.75 (dd, 7=39.3, 10.8 Hz, 2H), 3.563.38 (m, 2H), 3.06 ( s, 0.4H), 2.92 (d,7= 13.0 Hz, 1H), 2.79 (s, 1H) 434 η ₂ ν ΧχΟΟΗ ₃ ^Λν'Ν—' O ΗΝ 1 378.2 1.88/G 6 8.61 (s, 1H), 8.40-8.38 (d, 7 = 8.6 Hz, 1H), 8.17 (s, 1H), 8.10-8.08 (m, 1H), 7.81-7.80 (d,7=2.4 Hz, 1H), 6.896.88 (d,7=2.4 Hz, 1H), 5.39 (s, 2H), 4.20 (s, 1H), 4.00-3.90 (m, 2H), 3.85-3.54 (m, 4H), 3.40 (s, 3H), 2.332.28 (m, 2H) 435 Η ₂ Ν k / x RSN ₃ ^Ν \ Κν ^Ν □ ky^N Ν- ¹ Ο ΗΝ Λ 364.3 0.63/Η 6 8.60 (s, 1H), 8.38-8.36 (d, 7 = 8.6 Hz, 1H), 8.17 (s, 1H), 8.10-8.07 (m, 1H), 7.81-7.80 (d,7=2.4 Hz, 1H), 6.896.88 (d,7=2.4 Hz, 1H), 5.19-5.19 (m, 2H), 4.50-4.44 (m, 2H), 4.30-4.27 (m, 1H), 4.10-4.08 (m , 2H), 4.02-3.98 (m, 2H), 3.48 (s, 3H) 436 η ₂ ν /0 ν u ^Ν \ 5 ΑΛ ΗΝ \ 364.2 1.07/Η 6 8.58 (s, 1H), 8.42-8.40 (d,7 = 8.5 Hz, 1H), 8.17 (s, 1H), 8.12-8.08 (m, 1H), 7.81-7.80 (d,7=2.4 Hz, 1H), 6.906.89 (d, 7= 2.4 Hz, 1H), 5.27-5.25 (t,7=6.1 Hz, 2H), 4.90-4.84 (m, 4H), 4.84 (s, 4H), 3.75 (s, 2H)

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437 nh ₂ ΛΑ IT T ^H AnAz \ । X=N 279.3 0.75/C δ 8.41 (d, 7= 2.6Hz, 1H), 8.26 (d, 7= 8.8Hz, 1H), 8.11 (d, 7= 2.0Hz, 1H), 7.97 (dd, 7=8.7, 1.9Hz, 1H) , 7.81 (d, 7= 1.8 Hz, 1H), 7.20 (s, 1H), 6.64-6.59 (m, 1H), 4.40 (s, 2H). 438 nh ₂ nAy HHT ^HAH 279.3 1.30/J δ 8.19 (d, 7= 8.4Hz, 1H), 8.09 (d,7= 1.5Hz, 1H), 7.99 (dd,7=8.4, 1.6Hz, 1H), 778 (d, 7= 2.4Hz, 1H) , 7.20 (s, 1H), 6.85 (d, 7= 2.3 Hz, 1H), 4.40 (s, 2H) 439 YH ₃ C LL Η ITH nW 307.4 0.73/C δ 8.24 (d, 7= 8.4Hz, 1H), 8.10 (d, 7= 1.7Hz, 1H), 8.00 (d, 7= 8.4Hz, 1H), 7.78 (dd, 7=2.4, 1.1Hz, 1H) , 7.33 (s, 1H), 6.85 (d, 7= 2.4 Hz, 1H), 4.60 (s, 2H), 2.97 (s, 6H) 440 h ₂ n nAAw ΛΛ ^ΝΗ oh H Ha YJ 308.1 0.82/H 6 8.07 (d, 7= 8.4 Hz, 1H), 7.97 (s, 1H), 7.75 - 7.66 (m, 2H), 6.76 (d, 7= 2.3 Hz, 1H), 6.56 (d, 7= 1.0 Hz, 1H), 3.70 (t, 7= 6.4 Hz, 2H), 3.002.90 (m, 2H), 2.08-2.00 (m, 2H) 441 (NJ T ^z > i ⁵ 1 O χ ⁴ (NJ ) ( FROM IZ / 'z 307.4 0.71/H δ 8.38 (d, 7= 8.8Hz, 1H), 8.20 (d,7= 1.6Hz, 1H), 8.03 (dd,7=8.7, 1.6Hz, 1H), 7.87 (d, 7= 2.3Hz, 1H) , 7.27 (s, 1H), 6.89 (d, 7= 2.3 Hz, 1H), 4.64 (d, 7 = 7.4 Hz, 2H), 4.39 (s, 2H), 1.47 (t, 7= 7.1 Hz, 3H) 442 Z ₄ \_/ T )----< u ΞΕΖ 3 o T 294.1 0.85/E δ 8.26 (d, 7= 8.4Hz, 1H), 8.05 (d,7= 1.5Hz, 1H), 7.96 (dd,7=8.4, 1.6Hz, 1H), 7.79 (d, 7= 2.4Hz, 1H) , 6.86-6.84 (m, 2H), 3.96 (t, 7= 6.6 Hz, 2H), 3.10-3.07 (m, 2H) 443 h ₂ n Ya o ^N " / - ⁴ -4 / And / NH H ~ CH ₃ h N-^ Z ^ yj 321.3 0.83/C δ 8.20 (d, 7= 8.4Hz, 1H), 8.05 (d,7= 1.5Hz, 1H), 7.95 (dd, 7=8.5, 1.6Hz, 1H), 7.77 (d, 7= 2.4Hz, 1H) , 6.93 (s, 1H), 6.82 (d, 7= 2.4 Hz, 1H), 4.58 (s, 2H), 3.66 (s, 3H)

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444 Z ₄ \ ' ^ZI Oy _z \ / T / \ ¹⁴⁰ .z y / Dg ^t ο ^ω IA° co Z 1 o co 335.4 1.06/C δ 8.41 (d, 7= 8.8 Hz, 1Η), 8.13 (d, J= 1.5 Hz, IH), 8.04 (dd,7=8.7, 1.6 Hz, IH), 7.78 (d, J= 2.3 Hz, IH) , 7.44 (s, IH), 6.87 (d, J= 2.3 Hz, IH), 4.83-4.67 (m, 4H), 3.02 (s, 6H), 1.54 (t, J= 7.1 Hz, ZN) 445 NH ₂ 0 nA ^h M L £ / CH ₃ 1J ^H \ । VN 321.1 1.56/F δ 8.38 (d, J= 2.5 Hz, IH), 8.23 (d, 7= 8.7 Hz, IH), 8.06 (s, IH), 7.90 (d, 7= 8.7 Hz, IH), 7.80 (d,7= 1.9 Hz, IH), 6.90 (s, IH), 6.63 - 6.57 (m, IH), 4.57 (s, 2H), 2.04 (s, 3H) 446 T О L i у z χ ^ζ Ά/ ZZ 308.1 0.95/Α δ 8.30 (dd, 7= 2.6, 0.7 Hz, IH), 8.13 (d, 7= 8.7 Hz, IH), 7.90 (d, 7= 2.2 Hz, IH), 7.78 (dd, 7= 1.8,0.6 Hz, IH), 7.69 (dd, 7= 8.7, 2.2 Hz, IH), 6.62 -6.53 (m, 2H), 3.70 (t, 7 = 6.4 Hz, 2H), 2.98 - 2.89 (m, 2H), 2.06-1.98 (m, 2H) 447 y H ₂ N YES ^0SNz \ / lG ^N f / y-NH 0 O HN - / 434.1 0.99/Η δ 8.14 (d, 7= 8.4Hz, IH), 8.01 (d,7= 1.5Hz, IH), 7.93 (dd, 7=8.4, 1.6Hz, IH), 7.77 (d, 7= 2.3Hz, IH) , 7.55 (s, IH), 6.81 (s, 2H), 4.08 (d,7= 2.0 Hz, ZN), 3.77 (td, 7= 7.1, 3.8 Hz, 2H), 3.15(t,7=7.0 Hz, 2H) 448 nh ₂ o nAH L £ / CH ₃ [ιΊΤ V Anz \ । VN 349.4 0.89/Η δ 8.44-8.25 (m, 2Η), 8.09 (d, 7= 1.8 Hz, IH), 7.95 (dd,7= 9.0, 1.8 Hz, IH), 7.81 (d,7= 1.6 Hz, IH), 7.03 ( s, IH), 6.65-6.58 (m, 1H), 4.63 (d,7 = 7.3 Hz, 4H), 2.05 (s, 3H), 1.54 (s, 3H) 449 T O I___ co | about x' CN ) f IZ Λ ζ 336.2 0.93/Η 6 8.34-8.31 (d, 1=8.7 Hz, IH), 8.06-7.98 (m, IH), 7.98-7.95 (d, 1=8.4 Hz, IH), 7.76-7.70 (d, 1=18.3 Hz, IH ), 6.87-6.83 (m, 2H), 4.67-4.59 (m, 2H), 3.77-3.73 (t, 1=12.3 Hz, 2H), 2.97-2.92 (t, 1=15.3 Hz, 2H), 2.08- 1.99 (m, 2H), 1.56-1.52 (t, 1=14.4 Hz, ZN) 450 C ^H 2 n ₃ C CH ₃ /όη I 1 Ν—' ⁿ jjT^ ⁷ ΝνζΑα Μ 323.2 2.01/J 6 8.76 (s, IH), 8.18-8.03 (m, 2H), 7.86 (dd, 7=59.7, 1.9 Hz, 2H), 6.82 (d, 7= 2.3 Hz, 1H), 4.54 (s, 2H), 1.30(s, 6H)

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451 U ^H 2 H ₃ C 5-on j G N-' n Ijj Μ 309.1 0.48/D 5 8.74 (s, 1H), 8.09 (d,7=8.2 Hz, 1H), 8.02 (s, 1H), 7.90 (d, J= 8.3 Hz, 1H), 7.81-7.72 (m, 1H), 6.82 ( d, 7= 2.4 Hz, 1H), 4.58 (dd,7= 13.4,3.5 Hz, 1H), 4.48 - 4.28 (m, 2H), 1.31 (d, 7=6.2 Hz, ZN) 452 η ₂ ν _κι on VZ ^N ' GCH, ΑΆ N^^A ³ N \—/ CH ₃ O ην-/ 337.4 2.16/F 5 8.60 (s, 1H), 7.97 (t,7= 11.7 Hz, 2H), 7.70 (s, 2H), 6.74 (s, 1H), 4.68-4.58 (m, 2H), 2.32 - 2.20 (m, 2H ), 1.32 (s, 6H) 453 nh ₂ he 1 X ν -\ ^CH z Η 1 νΑΑ Μ 309.4 1.14/Α 5 8.63 (s, 1H), 7.98 (t, 7 = 14.7 Hz, 2H), 7.71 (s, 2H), 6.74 (s, 1H), 4.78 (qd, 7=7.0, 4.5 Hz, 1H), 4.17- 3.89 (m, 2H), 1.68 (d, 7= 6.9 Hz, ZN). 454 ΝΗ ₂ OH ^{n CHz} Μ 323.4 1.17/Α 5 8.73 (s, 1H), 8.04 (t, 7 = 10.8 Hz, 2H), 7.80 (d,7= 29.6 Hz, 2H), 6.78 (s, 1H), 5.05 -4.95 (m, lH), 3.58( dt, J= 11.1.5.5 Hz, 1H), 3.393.34 (m, 1H), 2.42-2.24 (m, 1H), 2.19-2.03 (m, 1H), 1.72 (d,7=6.7 Hz, ZN) 455 νη ₂ μ 294.2 0.57/D 5 12.78 (s, 1H), 7.84 (d,7= 8.0 Hz, 2H), 7.77 (s, 1H), 7.61-7.64 (m,7= 12.4, 1.8 Hz, 1H), 7.52 (s, 2H), 6.69 (s, 1H), 6.60 (s, 2H), 5.05 (t, 7= 5.2 Hz, 1H), 4.22 (t, 7= 5.4 Hz, 2H), 3.76-3.80 (m, 2H) 456 CO ο ο ζ Αϊ ζ-λΑα τ 308.3 0.92/Η 5 13.24-12.80 (m, 1H), 7.84 - 7.52 (m, 6H), 6.68 (s, 1H), 6.59 (s, 2H), 4.36 (t, 7= 5.1 Hz, 2H), 3.74 (t, 7 = 5.1Hz, 2H), 3.27(s, 3H)

Example 457 Preparation of 7-(1H-pyrazol-3-yl)-2H-pyrazolo[4,3-c]quinoline-4-amine

To a suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo-[4,3-c]quinolin-4amine (30 mg, 0.0 9 mmol) in DCM (150 µl) was added TFA (150 µl). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude material was taken up in DCM (300 µl) and concentrated, then dissolved in DMF (2 ml), filtered (syringe filter with 0.45 µm Acrodisc nylon membrane) and purified by prep HPLC to give 7-(1H-pyrazole-3- yl)-2H-pyrazolo[4,3-c]quinoline-4-amine (13.6 mg, 60.6%). 1H NMR (500 MHz, DMSO-d6) δ 14.35-13.89 (m, 1H), 13.24-12.82 (m, 1H), 8.37 (br s, 1H), 8.13 (d, J=8.3 Hz, 1H), 8.04 -7.94 (m, 1H), 7.86-7.68 (m, 2H), 7.52-7.03 (m, 2H), 6.80 (br s, 1H). Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). m/z 250.9 [M+H]+; RT: 0.89 min.

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Example 458 Preparation of 2-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-N,N-dimethylacetamide, TFA

Suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrazolo-[4,3-c]quinoline-4amine (34 mg, 0.102 mmol), carbonate cesium (83 mg, 0.254 mmol) and 2-chloro-N,N-dimethylacetamide (24.72 mg, 0.203 mmol) in DMFA (1 ml) was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (10 ml) and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was then treated with EtOAc (1 ml). 4N HCl in dioxane (0.5 ml) was added. The resulting mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The crude material was purified by preparative LC/MS under the following conditions: column: XBridge C18, 200x19 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 min hold at 0% B, 0-28% B for 25 min, then 0 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated based on MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation. Analytical method LC/MS was used to determine the final purity. Injection Conditions 1: Column: Waters XBridge 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm). LCMS M+H: 336.26; retention time: 1.04 min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.18 (m, 2H), 7.94 (br d, J=7.9 Hz, 1H), 7.88 (br s, 1H), 6.84 ( s, 1H), 5.63 (s, 2H), 3.13 (s, 3H), 2.92 (s, 3H).

An alternative route for the preparation of 2-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)-N,N-dimethylacetamide.

Step 1 Ethyl 2-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3c]quinolin-2-yl )acetate.

Suspension of 7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrazolo-[4,3-c]quinoline-4amine (700 mg, 2.093 mmol), carbonate cesium (1705 mg, 5.23 mmol) and ethyl 2-chloroacetate (513 mg, 4.19 mmol) in DMF (6 ml) were stirred at room temperature for 3 hours, after which LC/MS showed complete conversion. The reaction was quenched with water (10 ml), extracted with 5% MeOH/DCM (3x). The combined organic layers were dried over Na ₂ SO ₄ , concentrated in vacuo and purified by flash chromatography (0-20% MeOH/DCM, 2N NH ₃ ) to give the desired isomer (550 mg, 62.5%). LC/MS M ⁺ =393.3.

Step 2 2-(4-Amino-7-(III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-acetic acid.

To a suspension of the acid obtained in step 1 in THF/MeOH (1:1, 12 ml) was added an aqueous solution of NaOH (2N, 2 ml). The mixture was stirred at room temperature for 3 hours before being concentrated in vacuo. Then a solution of HCl in Et ₂ O (2N, 8 ml) was added. The resulting suspension was stirred at room temperature for 30 min, then concentrated and neutralized to pH 6 with an aqueous solution of NaHCO ₃ . The product was collected by vacuum filtration, washed with Et2O and water, and dried under vacuum to give 2-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinoline-2

- 175 042018 yl)acetic acid as a white solid (350 mg, 85%). LCMS M ⁺ =309.2. 1H NMR (400 MHz, DMSO-d6) shift 9.06-8.68 (m, 2H), 8.28-7.59 (m, 4H), 6.77 (s, 1H), 5.36 (s, 2H).

Step 3 2-(4-Amino-7-(III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-N,N-dimethylacetamide.

Suspension of 2-(4-amino-7-(III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-acetic acid (20 mg, 0.065 mmol), Hunig's base ( 68.0 µl, 0.389 mmol) in DMF (0.8 ml) was sonicated for 2 min before dimethylamine solution (97 µl, 0.195 mmol, 2 M in THF) and HATU (24.67 mg, 0.065 mmol) were added. The mixture was stirred at room temperature for 1 hour before additional HATU (24.67 mg, 0.065 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The crude product was purified by preparative HPLC to give 2-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3c]quinolin-2-yl)--K,K-dimethylacetamide. LC/MS M ⁺ =336.1.

Compounds of examples 459-487 were prepared according to synthetic procedures similar to those described for the compounds of previous examples from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

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Etc. No. Structure LC/MS [M+H]+ RT (min) Ή NMR, 400 MHz, Methanol A unless otherwise noted 459 U ⁿ 2 H ₃ CO OH hn' J 338.9 1.01 5 8.67 (s, 1H), 7.95 (d, 7=8.1 Hz, 1H), 7.89 (s, 1H), 7.747.65 (br, 1H), 7.62 (br d, 7=7.2 Hz, 1H), 6.74 (s, 1H), 6.77 (br s, 2H), 5.03-4.89 (br, 1H), 4.59 (dd, 7=14.1, 3.4 Hz, 1H), 4.44 (dd, 7=13.8, 7.7 Hz, 1H) , 3.73 (dq,7=8.0, 4.2 Hz, 1H), 3.56 - 3.48 (w, 2H), 3.22 (s, ZH) 460 z o / z^ / z zPAAx t ^z \A z T 332.3 0.99 5 8.93 (s, 1Н), 8.20 (d, 7=8.2 Hz, 1Н), 8.11 (brs, 1Н), 7.92 (brd,7=8.0 Hz, 1Н), 7.86 (br s, 1Н), 6.82 (d ,7=2.0 Hz, 1Н), 4.56 (t, 7=6.9 Hz, 2Н), 2.59 (t, 7=7.1 Hz, 2Н), 2.161.97 (br, 2Н), 1.70-1.54 (br, 2Н) 461 O P ^H 3 h ₂ n A—-NH N^y^NLAn O HN \ 322.2 0.95 5 8.98 (s, 1H), 8.37 (brd, 7=4.3 Hz, 1H), 8.19 (brd, 7=7.9 Hz, 1H), 8.14 (brs, 1H), 7.93 (brd, 7=7.3 Hz, 1H) , 7.88 (brd, 7=1.2 Hz, 1Н), 6.83 (s, 1Н), 5.26 (s, 2Н), 2.70 (d, 7=4.3 Hz, ZN) 462 CM i / z Va z-XAAa t ^z ΆΑ z T 322.3 0.94 5 8.92 (s, 1Н), 8.19 (brd, 7=8.2 Hz, 1Н), 8.12 (brs, 1Н), 7.93 (brd,7=7.9 Hz, 1Н), 7.87 (br s, 1Н), 7.50 (br s, 1Н), 6.98 (br s, 1Н), 6.82 (brs, 1Н), 4.68 (brt, 7=6.3 Hz, 2Н), 2.83 (brt, 7=6.3 Hz, 2Н) 463 T z /Aha VF y ^z YA 2 o o co 357.2 1.0 5 9.01 (s, 1Н), 8.21 (brd, 7=8.2 Hz, 1Н), 8.13 (brs, 1Н), 7.94 (brd,7=7.6 Hz, 1Н), 7.87 (brs, 1Н), 6.83 (s, 1Н), 4.99 (brt, 7=6.6 Hz, 2Н), 3.97-3.83 (br, 2Н), 3.07 (s, 2Н) 464 Va Nie A I 330.3 0.97 5 8.65 (s, 1H), 8.11 (d, 7=8.2 Hz, 1H), 7.90 (s, 1H), 7.827.71 (br, 1H), 7.67 (br d, 7=7.2 Hz, 1H), 6.78 (d, 7=1.9 Hz, 1H), 4.64 (s, 2H), 1.521.36 (w, 4H)

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465 ¢0 τ A Ο=ω t and ° A o'' \ - X'ud * ^ζ Ζ t 400.1 1.08 5 8.93 (s, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.11 (brs, 1H), 7.93 (brd, 7=8.4 Hz, 1H), 7.85 (br s, 1H), 7.37 (d , 7=8.5 Hz, 1H), 6.83 (d, 7=2.1 Hz, 1H), 4.53 (brdd, 7=13.6, 4.9 Hz, 1H), 4.41 (brdd,7=13.8, 7.9 Hz, 1H), 3.97 - 3.84 (m, 1H), 2.97-2.84 (m, 1H), 2.842.72 (m, 1H), 1.23 (brd, 7=6.6 Hz, VN), 0.99 (t, 7=7.3 Hz, VN) 466 Ν ^Η 2 CN 1 An-/ /у ^N hn JT 344.1 1.03 δ 13.19-12.78 (m, 1H), 8.60 (s, 1H), 8.11 (d, 7=8.0 Hz, 1H), 7.91 (brs, 1H), 7.817.61 (m, 2H), 7.38-7.04 (m , 2H), 6.76 (s, 1H), 4.45 (s, 2H), 2.65 (s, 2H), 0.93 - 0.89 (m, 2H), 0.75 - 0.70 (m, 2H) 467 Ν ^η 2 _μ _ CH ₃ XAo Ν Jj D > γ ^Hsc ° 431.0 1.33 δ 8.48 (s, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.19 (d, 7=8.0 Hz, 1H), 7.88 (brs, 1H), 7.80 - 7.59 (m, 2H), 7.17-6.95 (m, 2H), 6.77 (d, 7=1.7 Hz, 1H), 4.70 (s, 2H), 2.49 (br s, 3H), 1.42 (s, 6H) 468 ZE Ζ Q v/y _z \_/ I )----\ ^w T ^ω 363.0 0.85 δ 13.37-13.14 (m, 2H), 8.31 -8.21 (m, 3H), 8.12 (s, 1H), 7.96 (brd, 7=8.0 Hz, 1H), 7.83 (s, 1H), 6.84 (d, 7 =1.9 Hz, 1H), 4.41 (brs, 2H), 3.84 -3.74(m, 4H), 3.21 -3.13 (m, 4H), 2.53 (brs, 3H) 469 N ^H 2 CH ₃ nAA^a xJ £jh hn'Y 363.2 0.89 δ 8.10 (d, 7=8.3Hz, 1H), 7.94 (s, 1H), 7.71 (brs, 1H), 7.68 (brd,7=8.0Hz, 1H), 6.76 (d, 7=1.9Hz, 1H) , 6.74-6.63 (m, 2H), 3.84-3.77 (m, 2H), 3.78 - 3.67 (m, 3H), 3.44 (br dd, 7=8.7, 4.3 Hz, 1H), 3.303.26 (m, 1H ), 2.41 (s, 3H), 1.98-1.92 (m, 1H), 1.741.65 (m, 1H) 470 CH ₃ N ^H 2 CH ₃ { 0 ML <YN JT ^H N-YkiX HN ^Z Ύ 363.1 1.13 δ 11.90-11.67 (m, 1H), 8.20 -8.11 (m, 1H), 7.90 (brs, 1H), 7.69 (brs, 1H), 7.667.60 (m, 1H), 6.74 (s, 1H), 6.21 (br s, 2H), 4.70-4.62 (m, 2H), 3.28-3.17 (m, 2H), 2.46 - 2.40 (m, 3H), 2.25 2.04 (m, 3H), 1.09-0.85 (m, 3H)

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471 τ ζ Cky _z \__/ ΞΕ /----\ ^Μ ΙΖ ζ/ 361.1 1.03 δ 8.18 (d, 7=8.3 Hz, 1H), 7.94 (s, 1H), 7.71 (s, 1H), 7.65 (br d, 7=7.5 Hz, 1H), 7.26-7.11 (m, 2H), 6.75 (s, 1H), 6.70 (s, 1H), 4.38 (s, 1H), 3.95 (brd, 7=7.6 Hz, 1H), 3.90-3.81 (m, 2H), 3.16 (s, 1H), 2.8O (brd, 7=9.3 Hz, 1H), 1.82 (brd, 7=9.0 Hz, 1H), 1.62 (brd, 7=9.3 Hz, 1H); two CH protons are not visible, probably due to overlap with suppressed water peak. 472 ΝΗ ₂ ^\.-'OSN ₃ ί] η νΎΟΖ ην'Ύ 362.9 0.95 δ 12.25-11.99 (m, 1H), 8.17 (d, 7=8.3 Hz, 1H), 7.93 (s, 1H), 7.70 (br s, 1H), 7.62 (br d, 7=8.1 Hz, 1H), 6.99-6.89 (m, 2H), 6.74 (d, 7=1.8 Hz, 1H), 6.66 (s, 1H), 3.94-3.86 (m, 1H), 3.72 (s, 2H), 3.193.12 (m, 4H), 2.72 (dd, 7=10.0.6.1 Hz, 1H), 2.62 (q, 7=7.6 Hz, 1H), 2.49 - 2.43 (m, 1H), 2.06- 1.97 (m, 1H), 1.72- 1.62 (m, 1H) 473 ΞΕ Ζ Ύ \_/ τ /----( ^Μ ΙΖ Ζ/Η%| 375.1 0.67 Ή NMR (500 MHz, DMSOd ₆ ) δ 11.99 - 11.91 (m, 1H), 8.14 (d, 7=8.3 Hz, 1H), 7.92 (s, 1H), 7.70 (br d, 7=2.2 Hz, 1H) , 7.63 (brd, 7=7.9 Hz, 1H), 6.74 (d, 7=2.0 Hz, 1H), 6.72 - 6.67 (m, 2H), 6.66 (s, 1H), 4.22 (brs, 2H), 3.61 ( s, 2H), 2.59 (br d, 7=10.6 Hz, 2H), 2.26 (br d, 7=9.8 Hz, 2H), 1.93 (q, 7=5.9 Hz, 2H), 1.75 - 1.69 (m, 2H ) 474 / -0 νη ₂ (γ\ όο^ ^1; J Τ ^Η ΗΝ Ύ 375.1 0.66 δ 12.36-11.99 (m, 1H), 8.19 (d, 7=8.3 Hz, 1H), 7.94 (s, 1H), 7.70 (br s, 1H), 7.65 (br d, 7=7.4 Hz, 1H), 7.10-7.00 (m, 2H), 6.75 (d, 7=1.9 Hz, 1H), 6.72 (s, 1H), 3.60-3.56 (m, 2H), 3.09(br s, 2H), 2.03 - 1.96 (m , 2H), 1.78 (brd, 7=7.2 Hz, 2H); four CH protons are not visible, probably due to overlap with the suppressed water peak.

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475 nh ₂ nF+Y SNz <Y ^N Η J ⁿ νΥΥ HN J 390.2 0.59 δ 12.32-12.11 (m, 1H), 8.18 (d, 7=8.3 Hz, 1H), 7.96 (brd, 7=6.1 Hz, 2H), 7.76-7.59 (m, 2H), 7.21-6.84 (m, 2H ), 6.75 (brd, 7=1.4 Hz, 1H), 6.70 (s, 1H), 4.15 (brdd, 7=8.8, 4.7 Hz, 1H), 3.803.68 (m, 2H), 2.84-2.76 (m, 1H), 2.67 - 2.60 (m, 1H), 2.32 (br dd, 7=9.4, 5.0 Hz, 1H), 2.16-2.06 (m, 1H), 1.76 (s, 3H), 1.64-1.52 (m, 1H ); one CH proton is not visible, probably due to overlap with the suppressed water peak. 476 νη ₂ ΖΥ Ν— ¹ Orv Ζγ + j ] ^н hn' j 333.2 0.92 δ 8.18 (d, 7=8.3 Hz, 1H), 7.95 (s, 1H), 7.70 (br s, 1H), 7.64 (brd,7=8.3 Hz, 1H), 7.14 (br d, 7=2.8 Hz, 2Н), 6.75 (d, 7=1.9 Hz, 1Н), 6.68 (s, 1Н), 3.75 (s, 2Н), 2.53 - 2.50 (br, 4Н), 1.73 (brs, 4Н) 477 nh ₂ γΚ juYz ^N /+Zn ί I ^H HN J 354.9 0.96 δ 12.25-12.13 (m, 1H), 8.14 (d, 7=8.5 Hz, 1H), 7.93 (s, 1H), 7.70 (br s, 1H), 7.63 (br d, 7=8.3 Hz, 1H), 6.95 (br s, 2H), 6.74 (d, 7=1.7 Hz, 1H), 6.70 (s, 1H), 3.89 (s, 2H), 3.70-3.62 (br, 4H) 478 NH ₂ Ilf H HO hn' j 377.3 0.64 δ 13.69-13.39 (m, 2H), 13.23-13.03 (br, 1H), 9.359.19 (br, 1H), 9.16-8.82 (br, 2H), 8.25 (brd,7=8.5 Hz, 1H), 8.19 (brs, 1H), 7.99 (br d, 7=8.0 Hz, 1H), 7.86 (br s, 1H), 7.26 (s, 1H), 6.84 (s, 1H), 4.85 - 4.68 (m, 1H), 4.40 (br s, 2H), 3.63-3.55 (m, 1H), 3.41-3.37 (m, 1H), 2.26-2.17 (m, 1H), 2.111.97 (m, 2H), 1.78-1.63 (m, 2H), 1.55 - 1.47 (m, 1H), 1.43 - 1.34 (m, 1H) 479 OCH ₃ nh ₂ y Ϊ fj H N-^X^ hn' j 349.1 1.07 δ 13.66-13.42 (m, 2H), 13.31-12.94 (m, 1H), 9.26 8.78 (m, 2H), 8.26 (d, 7=8.3 Hz, 1H), 8.17 (brs, 1H), 7.98 (brd, 7=8.3 Hz, 1H), 7.84 (br s, 1H), 7.26 (s, 1H), 6.83 (d, 7=2.2 Hz, 1H), 4.60 (br s, 2H), 4.34 (brd,7=1.9 Hz, 2H), 4.28-4.18 (m, 2H), 4.07-3.96 (m, 1H), 3.27-

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3.22(m, 3H) 480 I z G ^z tAk \ ( M IZ O I 349.1 0.56 δ 8.16 (d, 7=8.3 Hz, 1H), 7.93 (s, 1H), 7.70 (br s, 1H), 7.62 (brd,7=8.4 Hz, 1H), 7.046.91 (m, 2H), 6.74 (d, 7=1.7 Hz, 1H), 6.65 (s, 1H), 4.22 (tt, 7=6.7, 3.4 Hz, 1H), 3.77 3.67 (m, 2H), 2.75 (br dd, 7=9.5, 6.3 Hz, 1H), 2.68 2.55 (m, 2H), 2.37 (dd, 7=9.7, 3.8 Hz, 1H), 2.08- 1.97 (m, 1H), 1.58 (td, 7=8.0, 4.6 Hz, 1H) 481 0 nh ₂ °*s-ch ₃ /—NH n YyA η T ⁿ hn' J 371.2 0.81 δ 13.10 (brd, 7=4.2 Hz, 1H), 12.83 (br s, 1H), 8.60 (td, 7=5.5, 2.8 Hz, 2H), 8.258.18 (m, 1H), 8.14 (brs, 1H) , 7.94 (br d, 7=7.3 Hz, 1H), 7.84 (brs, 1H), 7.22 (t, 7=5.7 Hz, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 3.37-3.31 (m, 2H), 3.00 (brt,7=7.3Hz, 2H), 2.91 (s, 3H) 482 I z Q O^Vz \_/ I IZ J ϊΆ / I 385.3 0.87 δ 13.20-13.01 (m, 1H), 12.85 (br s, 1H), 8.84-8.34 (m, 2H), 8.21 (d, 7=8.3 Hz, 1H), 8.17-8.09 (m, 1H), 7.94 ( brd, 7=8.9Hz, 1H), 7.84(brs, 1H), 7.24(brt, 7=5.8Hz, 1H), 6.89(s, 1H), 6.82(s, 1H), 3.32(q, 7=6.9 Hz, 2H), 3.03 - 2.95 (m, 4H), 1.15 (t, 7=7.4 Hz, ZN) 483 „ 9 ch ₃ nh ₂ °*!Ts ^{3 SNz} <Y ^N Η T ^h HN Ύ 399.2 0.95 δ 13.17 (brs, 1H), 13.09 (br d,7=0.8 Hz, 1H), 12.81 (brs, 1H), 8.82 - 8.42 (m, 2H), 8.26 - 8.20 (m, 1H), 8.16 (br s , 1H), 7.96 (br d, 7=7.4 Hz, 1H), 7.86 (br s, 1H), 7.23 (t, 7=5.8 Hz, 1H), 6.91 (s, 1H), 6.82 (brs, 1H) , 3.32-3.24 (m, 1H), 3.21-3.14 (m,2H), 2.99 (brt, 7=7.2Hz, 2H), 1.21 (d, 7=6.6Hz, 6H) 484 nh ₂ °4~0 JJ H n^xAA hn' jT 432.9 1.23 δ 13.17 (brs, 1H), 13.1213.05 (m, 1H), 12.74 (brs, 1H), 8.73 - 8.48 (m, 2H), 8.22-8.13 (m, 2H), 7.94 (br d, 7=9.4 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.78 (br d, 7=7.2 Hz, 2H), 7.60-7.51 (m, 3H), 6.84 (s, 1H), 6.81 (s, 1H), 3.15 (q, 7=6.8Hz, 2H), 2.93

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(brt, 7=7.3Hz, 2H)

13.28 (brs, 1Н), 13.1513.02 (br, 1Н), 12.87 (brs, 1Н), 8.73 (brt, 7=5.8 Hz, 1Н), 8.79 - 8.54 (m, 2Н), 8.28 - 8.23 (t, 2Н), 8.15 (br s, 1Н), 7.95 (brd, 7=8.4 Hz, 1Н), 7.85 (brs, 1Н), 6.88 (s, 1Н), 6.82 (d, 7=1.9 Hz, 1Н), 3.65 (q, 7=7.1Hz, 2H), 3.07 (brt,7=7.2Hz, 2H)_______

8.20 (d, 7=8.4 Hz, 1H), 7.92 (s, 1H), 7.74-7.62 (m, 2H), 6.77 (d, 7=1.8 Hz, 1H), 6.356.25 (br, 2H), 3.65 (s, 2H), 3.60-3.57 (br, 4H), 2.45 (br s, 4H)

8.81 - 8.39 (br, 2H), 8.26 (d, 7=8.3 Hz, 1H), 8.18 (s, 1H), 8.01 (d, 7=8.5 Hz, 1H), 7.85 (brs, 1H), 6.86 (d , 7=2.2 Hz, 1Н), 4.40 (s, 2Н), 3.983.88 (br, ZN), 3.82 (dd, 7=10.3, 5.9 Hz, 1Н), 3.713.65 (br, 1Н), 2.37 - 2.25 (w, 1H), 2.11 -2.02 (w, 1H)

3-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-N,N,2

Example 488 Preparation of trimethylpropanamide, TFA

Stage 1

Obtaining methyl-3 - (4-amino-7- (1 - (tetrahydro-2H-pyran-2-yl) -1 H-pyrazol-5 -yl) -2H pyrazolo[4,3-c] quinolin-2-yl )-2-methylpropanoate.

suspension

7-(1-(tetrahydro-2H-pyran-2-yl)-III-pyrazol-5-yl)-2H-pyrazolo-[4,3-c]quinoline-4 amine (0.2 g, 0.598 mmol) and cesium carbonate (0.585 g, 1.794 mmol) in DMF (1.994 ml) was stirred for a short period of time (~2 min), then treated with methyl (R)-3-6pom-2-methylpropanoate (0.178 g, 0.96 mol). Then the reaction mixture was heated to 60°C and stirred. After 5 hours the reaction mixture was treated with 0.1 g additional cesium carbonate and 0.1 g additional methyl (R)-3-bromo-2-methylpropanoate. Stirring at 60°C was continued after which the reaction mixture was poured into water and the pH was adjusted to ~6. The resulting mixture was extracted twice with EtOAc and the combined organic extract was dried, concentrated and purified by silica gel chromatography (50-100% THF-hexane) to give methyl 3-(4-amino-7-(1(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methylpropanoate (195 mg, 0.449 mmol, 75% yield) as colorless glass. Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). RT: 0.69 min. m/z 435.3 [M+H]+.

Step 2. Preparation of 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl )-2-methylpropanoic acid.

Methyl 3-(4-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4.3

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c]quinolin-2-yl)-2-methylpropanoate (190 mg, 0.437 mmol) in THF (2.2 ml) was treated with aqueous lithium hydroxide (2.186 ml, 2.186 mmol) followed by 0.6 ml MeOH. The reaction mixture was heated to 60° C. and stirred for 3 hours. Most of the organic solvent was removed under nitrogen flow, and the residue was diluted with 2 ml of water and filtered. The filtrate was adjusted to pH ~5.5 with ice cold HOAc and the resulting precipitate was filtered, washed with water and air dried to give 3-(4-amino-7-(1(tetrahydro-2H-pyran-2-yl)-1H-pyrazole -5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methylpropanoic acid (135 mg, 0.321 mmol, 73.4% yield) as a white powder. Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). RT: 0.63 min. m/z 421.2 [M+H]+.

Step 3. Preparation of 3-(4-amino-7-(III-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2-yl)-K,K,2trimethylpropanamide, TFA.

3-(4-Amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin2-yl)-2 solution -methylpropanoic acid (18 mg, 0.043 mmol) and dimethylamine ((2 M in THF), 86 μl, 0.171 mmol) in DMF (214 μl) were treated with BOP (22.72 mg, 0.051 mmol) and the resulting solution was stirred for 1 h at room temperature. The reaction mixture was then treated with 0.8 ml TFA-DCM (1:1) and stirred for 2 hours at room temperature. The reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC. Concentration of the appropriate fractions provided 3-(4-amino-7-(1H-pyrazol-5-yl)-2H-pyrazolo[4,3-c]quinolin-2yl)-K,K,2-trimethylpropanamide, TFA (10 mg, 49%) as a colorless solid. Analytical LC/MS conditions: column: Acquity UPLC VEN C18, 2.1 x 50 mm, particles 1.7 µm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm). RT: 0.56 min. m/z 364.1 [M+H] ⁺ . 1Н NMR (400 MHz, MeOH-d ₄ ) δ 8.70 (s, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.01 (s, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 4.63 (ABq, J _AB =13.3 Hz, J _AX =9.4 Hz, J _BX =4.9 Hz, Δν=109 Hz , 2Н), 3.773.87 (m, 1H), 3.07 (s, 3H), 2.89 (s, 3H), 1.28 (d, J=6.9 Hz, 3H).

The compounds of examples 489-624 were prepared according to synthetic procedures similar to those described in the previous examples from the appropriate starting materials. Analytical LC/MS conditions: column: Waters XBridge C18, 2.1 x 50 mm, particles 1.7 µm; 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 0.50 min at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Analytical LC/MS conditions for the compounds of examples 489 and 612: column: Acquity UPLC BEN C18, 2.1 x 50 mm, particles 1.7 μm; mobile phase A: water with 0.05% trifluoroacetic acid; mobile phase B: acetonitrile with 0.05% trifluoroacetic acid; temperature: 50°C; gradient: 2 to 98% B over 1 min, then hold 0.50 min at 98% B; flow rate: 0.8 ml/min; detection: MS and UV (254 nm).

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Etc. No. Structure LC/MS [Μ+Η] ⁺ RT (min) Ή NMR (500 MHz, DMSO-d ₆ ) 489 ^ ⁿ 2 n ₃ co, OH ΪΠΚνΑ Ku ^Ν nAA hn' Ύ 339.1 0.51 δ 13.05 (s, 1H), 9.78-9.61 (m, 1H), 8.96 (s, 1H), 8.65 8.51 (m, 1H), 8.21 (d, 7=8.2 Hz, 1H), 8.12 (s, 1H) , 7.93 (dd, 7=8.2, 1.4Hz, 1H), 7.85 (d, 7=1.8Hz, 1H), 6.82 (d, 7=2.2Hz, 1H), 4.67 (dd, 7=14.0, 3.5Hz, 1H), 4.53 (dd, 7=14.1, 7.7 Hz, 1H), 3.75 3.68 (m, 1H), 3.53 (d, 7=5.0 Hz, 2H), 3.26 (s, 3H) 490 χ ^{4 ζτ} A 'ζ t 375.1 0.63 δ 12.19-11.97 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.69 (br s, 1H), 7.60 (br d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.73 - 6.67 (m, 2H), 6.63 (s, 1H), 3.71 -3.63 (m, 6H), 2.72 (br s, 2H), 2.69 - 2.63 (m, 2H), 2.31 (brd, J=7.9Hz, 2H) 491 H ₃ C AK j T ^N Νχ/X® HN J 363.1 0.97 δ 8.21 (d, 1=8.0Hz, 1H), 7.97 (brd, J=2.8Hz, 1H), 7.887.57 (m, 2H), 7.28 - 6.90 (m, 2H), 6.74 (brd, 1=9.1 Hz, 2H), 3.86 (td, J=8.4, 4.4 Hz, 1H), 3.82 -3.77 (m, 1H), 3.72 -3.58 (m, 4H), 3.23-3.15 (m, lH), 2.14(s, 3H), 2.08 1.99 (m, 1H), 1.88 (dq, J=12.6, 7.6 Hz, 1H) 492 k° νη ₂ 22 jrK j Τ ^Η ν^222 hn' j 375.1 0.95 δ 8.16 (brd, J=8.3 Hz, 1H), 7.95 (brs, 1H), 7.71 (brs, 1H), 7.66 (brd, J=8.3 Hz, 1H), 7.34-7.15 (m, 2H), 6.76 ( s, 1H), 6.69 (s, 1H), 3.71 (s, 2H), 3.65 -3.61 (m, 2H), 3.24 -3.19(m, 2H), 2.01 (brt, J=6.9 Hz, 2H); four CH protons are not visible, probably due to overlap with the suppressed water peak. 493 I ζ 2 QV \_/ I / \ ¹⁴³ ο Υ η ο 402.3 1.11 δ 11.95 (brs, 1H), 8.44 (s, 1H), 8.35 (brt, J=5.6 Hz. 1H), 8.06 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.75 - 7.65 ( m, 1H), 7.64–7.55 (m, 1H), 6.73 (s, 1H), 6.57–6.51 (m, 3H), 3.65–3.58 (m, 2H), 3.03–2.98 (m, 2H), 2.44 ( s, 3H)

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494 IN ₂ /—ON ΗΝ^ ϊ TU^ Ν Η Τ ⁿ Ν-α^Α hn' J 323.2 0.87 δ 8.18 (brd, J=8.3 Hz, 1H), 8.06-7.98 (m, 1H), 7.85 7.69 (m, 2H), 6.84 (brs, 1H), 6.77 (brs, 1H), 4.81-4.62 (m, 1H), 4.00 (br s, 2H), 3.57 -3.51 (m, 2H), 2.74 (br s, 2H) 495 Τ ζ Ui /------\ ¹⁴³ ω ° 1 ο 418.2 0.99 5 12.12-12.00 (m, 1H), 8.49 (brt, 1=5.6Hz, 1H), 8.108.06 (m, 2H), 7.92 (s, 1H), 7.69 (br s, 1H), 7.63 (br d , J=8.5 Hz, 1H), 6.82 (brs, 2H), 6.73 (d,J=1.7r ₄ , 1H), 6.56 (s, 1H), 3.69 -3.62 (m, 2H), 3.04 (brt, J =7.6Hz, 2H), 2.69(s, 3H) 496 νη _{2 f} N0yA ^N He Ν^><Α ην' Jj 325.3 0.55 5 8.22 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.83 (br s, 1H), 7.25 (s, 1H), 6.84 (d , J=2.2 Hz, 1H), 4.75 (dt, J=46.8, 4.4 Hz, 2H), 4.44 (s, 2H), 3.43 -3.34 (m, 2H) 497 Ν ^η 2 cf ₃ UO ί Τ ^Η ην' Ύ 361.1 1.18 5 13.24 (s, 1H), 12.95 (brs, 1H), 8.93 - 8.52 (m, 2H), 8.28 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.83 (d, 1=1.9Hz, 1H), 7.04 (s, 1H), 6.82 (d, J=2.2 Hz, 1H), 4.05 (s, 2H), 3.44-3.35 (m, 2H ) 498 I ζ £? Uz X / Μ ΙΖ ΖΤ ω οL 1 ζ Ο ο 415.0 1.09 5 13.15 (brs, 1H), 12.85 (s, 1H), 8.22 (d, J=8.5 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.26 (br d, J=5.5 Hz, 1H), 6.90 (s, 1H), 6.82 (d, 1=2.1Hz, 1H), 3.623.59 (m, 2H), 3.36-3.31 (m, 2H), 3.27 (brt, J=6.1Hz, 2H), 3.20 (s, 3H), 2.98 (brt, J=7.2Hz, 2H) 499 νη ₂ ^ ^νη ϊ TU-/ Ν /=< GG ^Η Ο ΗΝ Τ \ \Α USN ₃ H ₃ C CH ₃ 454.0 1.50 5 13.25 (brd, J=4.7Hz, 1H), 12.93 (s, 1H), 8.66 (brt, 1=5.9Hz, 1H), 8.86 - 8.48 (m, 2H), 8.26 (brd, J=8.3Hz, 1H), 8.15 (s, 1H), 7.95 (brd, J=8.2 Hz, 1H), 7.92 - 7.88 (m, 1H), 7.86 -7.82 (m, 2H), 7.61 (d, J=7.9 Hz, 1H ), 6.94 (s, 1H), 6.82 (d,J=1.8r ₄ , 1H), 3.75 (q, J=7.0Hz, 2H), 3.12 (brt, 1=7.1Hz,2H), 1.27 (s, 9H)

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500 I ζ Q Cp ₂ \_/ I IZ r 1 o 388.0 1.04 5 8.85 (brt, 1=5.7Hz, 1H), 8.52 - 8.46 (m, 1H), 8.07 (d, J=8.3Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.70 ( br s, 1H), 7.66 (brd, J=8.2 Hz, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 3.73 -3.57 (m, 2H), 3.02 (br t, J=7.3 Hz , 2H) 501 nh _{2 o} TRU ίΡΙ^ O nJJ ⁰ HN J 392.3 1.05 5 8.51 (s, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.75 7.68 (m, 1H), 7.65 - 7.58 (m, 1H), 6.75 (d, 1= 1.8Hz, 1H), 4.64 (brt, J=6.3Hz, 2H), 3.05 (brt, J=6.4Hz, 2H); eight CH protons are not visible, probably due to overlap with the suppressed water peak. 502 <3 Pnh ₂ N*V\^ jpj ^N HN J 336.2 0.97 5 8.47 (s, 1Н), 8.08 (d, J=8.0 Hz, 1Н), 7.87 (s, 1Н), 7.70 (br s, 1Н), 7.62 (brd, J=8.3 Hz, 1Н), 7.35 (brs , 1Н), 6.966.84 (br, 2Н), 6.80 (brs, 1Н), 6.75 (d, 1=1.9Hz, 1Н), 4.41 (brt, J=6.5 Hz, 2Н), 2.162.07 (br, 4H) 503 nh ₂ o N^P^X / λ 1 N—' N^ .DX 3 hn' j 398.3 0.92 5 8.48 (s, 1Н), 8.06 (d, J=8.0 Hz, 1Н), 7.86 (s, 1Н), 7.70 (br s, 1Н), 7.61 (brd, J=8.0 Hz, 1Н), 6.91 (brs , 2Н), 6.75 (d, 1=1.7Hz, 1Н), 4.63 (t, J=6.5 Hz, 2Н), 4.57 (brt, J=12.2 Hz, 2Н), 4.27 (brt, J=12.5 Hz, 2Н ), 2.89 (t, J=6.5 Hz, 2H) 504 nh ₂ o nP+A / \ 1 1 N^ NH il ^N ' X nPP hn' j 376.3 1.13 5 13.37-13.01 (br, 1Н), 9.73 - 9.58 (br, 1Н), 9.04 - 8.94 (br, 1Н), 8.90 (s, 1Н), 8.25 (br d, J=7.7 Hz, 1Н), 8.17 ( brd, 1=8.2Hz, 1H), 8.10 (brs, 1H), 7.92 (brd, 1=8.2Hz, 1H), 7.84 (brs, 1H), 6.81 (s, 1H), 4.72 -4.65 (m, 2H ), 4.21 -4.10(m, 1H), 2.77 (brt, J=6.3 Hz, 2H), 2.14-2.05 (m, 2H), 1.87 - 1.69 (m, 2H), 1.62 - 1.55 (m, 2H) 505 nh ₂ o Ap ^N 'O hn' J ^ch z 405.3 0.92 5 8.50 (s, 1H), 8.07 (d, J=8.0Hz, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.62 (brd, 1=8.0Hz, 1H), 7.07 - 6.88 ( m, 2H), 6.74 (d, 1=1.9Hz, 1H), 4.63 (brt, J=6.3Hz, 2H), 3.44 -3.40 (m, 2H), 3.40 -3.36 (m, J=4.7Hz,

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2H), 3.03 (brt, J=6.5 Hz, 2H), 2.20-2.16 (m, 4H), 2.09 (s, 3H) 506 nh _{2 0} PjAA M-CH ₃ AA ^N ' H ₃ c hn' J 350.0 1.07 5 8.63 (brs, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.82 - 7.62 (m, 2H), 6.76 (s, 1H), 4.64 (brt, J =6.3Hz, 2H), 3.04(brt, J=6.3Hz, 2H), 2.94(s, 3H),2.81(s, 3H) 507 NH ₂ 0 N^A^A / \ IN—' NH rSf ⁿ C hn^A O 413.3 0.95 5 8.61 (brt, J=6.1 Hz, 1H), 8.45 (s, 1H), 8.40 (brd, J=4.4 Hz, 1H), 8.08 (d,J=8.ir ₄ , 1H), 7.89 (s, 1H), 7.71 (br s, 1H), 7.62 (brd, 1=8.4Hz, 1H), 7.39 (td, J=7.6, 1.6 Hz, 1H), 7.18-7.12 (m, 1H), 7.01 - 6.92 ( m, 2H), 6.89 (br d, J=7.8 Hz, 1H), 6.76 (d, J=1.7 Hz, 1H), 4.68 (brt, J=6.3 Hz, 2H), 4.32 (d, J=6.0 Hz , 2H), 2.93 (brt, J=6.4Hz, 2H) 508 nh _{2 o} n^A^x / \ IN—, AA E nAA hn' A 376.1 1.18 5 8.51 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.78 7.57 (m, 2H), 6.92 (br s, 2H), 6.75 (s, 1H), 4.64 (t, J=6.5Hz, 2H), 3.28 (brt, J=6.7Hz, 2H), 2.96 (brt, J=6.3Hz, 2H), 1.81 (quin, J=6.7Hz, 2H), 1.76- 1.66 (m, 2H); two CH protons are not visible, probably due to overlap with the suppressed water peak. 509 nh ₂ n CUP fy ^N CH ₃ ³ nA^ ^HN 'A 390.3 1.03 5 8.72 (s, 1Н), 8.07 (d, J=8.3 Hz, 1Н), 7.88 (s, 1Н), 7.71 (br s, 1Н), 7.63 (brd, J=8.0 Hz, 1Н), 7.04 - 6.87 (brs, 2H), 6.75 (d, 1=1.9Hz, 1H), 3.39 (brs, 2H), 2.34 (brs, 2H), 1.84 (s, 6H), 1.57 (brs, 4H) 510 nh ₂ o / \ f 1 n^ nh Αα ^ν ' H ₃ c-( N./U ^CH3 HN j 364.2 1.08 5 8.45 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.71 (brs, 1H), 7.64 (brd, 1=8.2Hz, 1H), 7.17- 6.94 (br, 2H), 6.75 (d, J=2.0 Hz, 1H), 4.61 (brt, J=6.5 Hz, 2H), 3.85 -3.75 (br, 1H), 2.72 (t, J=6.5 Hz, 2H ), 0.95 (d, J=6.6 Hz, 6Н)

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511 NH _{2 0} ΐ ν^Λη ^H0 hn'JT 366.3 0.94 5 13.29 - 13.05 (m, 1H), 9.74 - 9.52 (m, 1H), 8.89 (s, 1H), 9.03 - 8.79 (m, 1H), 8.18 (d, 1=8.2Hz, 1H), 8.09 (brs , 1H), 8.03 (brt, J=5.6 Hz, 1H), 7.91 (brd, J=8.2 Hz, 1H), 7.84 (brs, 1H), 6.81 (d, J=2.1 Hz, 1H), 4.68 (brt , J=6.4Hz, 2H), 3.34 (brt, J=6.0Hz, 2H), 3.10 (q, J=6.0Hz, 2H), 2.82 (t, J=6.4Hz, 2H) 512 nh _{2 0} N^A^ / \ 1 N—' A ⁴ ' N^Λ OH hn' J 377.9 0.96 5 8.52 (s, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.88 (s, 1H), 7.76 7.61 (m, 2H), 6.76 (d, J=1.9 Hz, 1H), 4.60 (brt , J=6.4 Hz, 2H), 4.36 (br s, 1H), 4.20 (br t, J=7.9 Hz, 1H), 4.01 (dd, J=9.7, 7.6 Hz, 1H), 3.79 (br dd, J =9.1.4.1 Hz, 1H), 2.77 (brt, J=6.4 Hz, 2H); one CH proton is not visible, probably due to overlap with the suppressed water peak. 513 nh ₂ 0 CH ₃ ^NH Chl/TcH3 fY ^N CH ₃ HN'JT 349.9 1.08 5 8.70 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.78 7.56 (m, 3H), 6.96 (br s, 2H), 6.75 (d, 1=1.7 Hz, 1Н), 2.59 (d, J=4.7 Hz, ZN), 1.86 (s, 6Н) 514 nh _{2 o} A ^F AAn Ach ₃ if 0 ⁿ ch ₃ hn' j 400.2 1.19 5 8.76 (s, 1Н), 8.09 (d, J=7.9 Hz, 1Н), 8.02 (t, J=5.8 Hz, 1Н), 7.90 (s, 1Н), 7.72 (br s, 1Н), 7.66 (brd , 1=7.6Hz, 1H), 6.76 (d, 1=1.5Hz, 1H), 5.97 (tt, J=56.2, 4.0 Hz, 1H), 1.89 (s, 6H); two CH protons are not visible, probably due to overlap with the suppressed water peak. 515 nh _{2 o} N^Y*^ / \ f 1 N— ⁷ NH .JJ' + hn' j ^f 386.3 1.09 5 8.46 (s, 1Н), 8.41 (brt, 1=5.8Hz, 1Н), 8.06 (d, J=8.2 Hz, 1Н), 7.87 (s, 1Н), 7.79 7.56 (m, 2Н), 6.75 (d , J=1.5 Hz, 1H), 5.95 (tt, J=55.8, 3.7 Hz, 1H), 4.64 (t, J=6.4 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H); two CH protons are not visible, probably due to overlap with the suppressed water peak.

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516 NH _{2 o} h-d Jj ^N nAA Ξ hn' j cn 401.3 1.07 5 8.54 (s, 1H), 8.07 (d, 1=8.1 Hz, 1H), 7.88 (brs, 1H), 7.82 -7.58 (m, 2H), 7.18-6.96 (m, 2H), 6.75 (s, 1H ), 4.64 (br t, 1=6.4 Hz, 2H), 3.76(br dd, 1=10.3, 7.4 Hz, 1H), 3.683.53 (m, 3H), 3.40 -3.34 (m, 1H), 3.07 - 2.94 (m, 2H), 2.29 - 2.00 (m, 2H) 517 nh _{2 0} nAy\ / ' I NH pp < »JU ^CH = hn' j 349.9 1.01 5 8.50 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.96 (brt, 1=5.2 Hz, 1H), 7.90 (brs, 1H), 7.837.60 (m, 2H), 7.48- 7.14 (m, 2H), 6.76 (s, 1H), 4.62 (t, 1=6.5 Hz, 2H), 3.08 -2.99 (m, 2H), 2.76 (t, 1=6.5 Hz, 2H), 0.93 (t , 1=7.2Hz, 3H) 518 nh ₂ F f \=J CH ₃ 401.1 1.02 5 13.32 (brs, 1H), 12.86 (s, 1H), 8.79 - 8.57 (m, 2H), 8.26 (d, 1=8.3 Hz, 1H), 8.17 - 8.10 (m, 2H), 7.95 (d, 1 =8.5 Hz, 1H), 7.83 (brs, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 6.89 (s, 1H), 6.81 (d, 1=2.2 Hz, 1H), 3.68 (s , 3H), 3.63 (q, 1=6.9Hz, 2H), 3.05 (brt, 1=7.3Hz, 2H) 519 nh ₂ mA-Λ ^NH N |GU-^ >0 <Z ^N /=( AU ⁿ O HN I \ Ά he 413.9 1.00 5 13.31 - 13.12 (m, 1H), 12.88 (s, 1H), 8.75 - 8.48 (m, 3H), 8.26 (d, 1=8.5 Hz, 1H), 8.14 (brs, 1H), 7.95 (brd, 1 =8.3Hz, 1H), 7.83(brs, 1H), 7.70(brt, 1=6.1Hz, 1H), 7.38-7.14(m, 1H), 6.90(s, 1H), 6.81(d, 1=1.9Hz , 1H), 6.74 (br d, J=6.6 Hz, 1H), 3.69 (q, 1=6.9 Hz, 2H), 3.08 (brt, 1=7.0 Hz, 2H) 520 F. nh ₂ A _f Uy n h T ^H n^UAU hn' D 343.2 0.91 5 11.98 (brs, 1H), 8.08 (d, 1=8.3 Hz, 1H), 7.92 (s, 1H), 7.69 (brs, 1H), 7.61 (brd, 1=8.0 Hz, 1H), 6.73 (d, 1=1.9Hz, 1H), 6.68-6.61(m, 3H), 6.03(tt, 1=56.4,4.1Hz, 1H), 3.92(s, 2H), 2.93(td, 1=16.0, 4.1Hz, 2H ) 521 oh nh _{2 o} Y AAn' Ach ₃ fY ^N CH ₃ nUA hn'Ύ 379.9 1.02 5 9.12 (s, 1H), 8.19 (d, 1=8.2 Hz, 1H), 8.11 (brs, 1H), 7.91 (brd, 1=8.5 Hz, 1H), 7.85 (br s, 1H), 7.81 (brt , 1=5.6 Hz, 1H), 6.81 (s, 1H), 3.15 (q, 1=6.3 Hz, 2H), 1.91 (s, 6H); two CH protons are not visible, probably due to

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overlap with suppressed peak of water. 522 Ν^χ- ΗΝ Jj μι _g sn ₃ he νη ₂ about ³ 7__ / DH / dChnz G|D ^N sn ₃ 408.1 1.19 δ 8.72 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.62 (brd, J=8.0 Hz, 1H), 6.99 - 6.90 (m, 3H), 6.75 (s, 1H), 3.28 (s, 2H), 1.87 (s, 6H), 1.17 (s, 6H) 523 ην' J nh _{2 o} g y ^N ch ₃ 412.0 1.23 6 8.77 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.89 (brs, 1H), 7.81-7.59(m, 2H), 7.14-6.99 (m, 2H), 6.76 (s, 1H ), 4.46 4.25 (m, 2H), 3.71 -3.55 (m, 2H), 1.86 (s, 6H) 524 hn'j nh ₂ o ODA · ^ν % ^η 3 J| Ί н ₃ 390.1 1.33 δ 8.66 (s, 1H), 8.06 (d, J=8.2Hz, 1H), 7.89 - 7.85 (m, 2H), 7.71 (brs, 1H), 7.63 (brd, 1=8.2Hz, 1H), 7.11 - 6.92 (m, 2H), 6.75 (d, J=2.1 Hz, 1H), 4.24-4.15 (m, 1H), 2.15 2.06 (m, 2H), 1.98 - 1.89 (m, 2H), 1.85 (s, 6H ), 1.63 - 1.54 (m, 2H) 525 ΗΝ' D T o h I oy ^ζ η Y ¹ O o C\ ) ( 427.1 1.05 δ 8.76 (s, 1H), 8.42 (brd, 1=4.4Hz, 1H), 8.27 (brt, 1=5.8Hz, 1H), 8.14 (d, J=8.3Hz, 1H), 7.88 (s, 1H) , 7.72 (br s, 1H), 7.68 - 7.64 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.24 7.18 (m, 1H), 6.92 (br s, 2H), 6.76 (d, 1=1.9Hz, 1H), 4.36(d, J=6.1Hz, 2H), 1.93(s, 6H) 526 ην'j n ₃ with nh ₂ y _w AxN /—S. ΓΑ ^ν Α'° dd 371.0 1.07 δ 9.01 (s, 1H), 8.21 (d, 7=8.1 Hz, 1H), 8.13 (brs, 1H), 7.94 (brd,7=7.3 Hz, 1H), 7.87 (br d, 7=1.9 Hz, 1H ), 6.83 (s, 1H), 4.98 (brt, 7=6.4 Hz, 2H), 3.88 (t, 7=6.6 Hz, 2H), 3.17 (q, 7=7.3 Hz, 2H), 1.23 (t, 7 =7.4 Hz, ZN) 527 ην'j ^U 2 u ΝΗ ₂ la 01 348.1 1.08 δ 9.06 (s, 1H), 8.19 (d, 7=8.2 Hz, 1H), 8.08 (brs, 1H), 7.92 (brd,7=8.3 Hz, 1H), 7.85 (br d, 7=1.0 Hz, 1H ), 7.17 (brs, 1H), 7.00 (brs, 1H), 6.83 (d, 7=2.1 Hz, 1H), 4.67 (s, 2H), 1.30-1.26 (m, 2H), 1.21 - 1.10

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(m, 2H); two protons are not visible, probably due to water suppression/water overlap. 528 NH ₂ 0 πχ nUU ⁷ hn' Ύ 362.2 1.09 5 8.47 (s, 1Н), 8.06 (d, 7=8.2 Hz, 1Н), 7.90 (s, 1Н), 7.72 (br d, 7=3.7 Hz, 1Н), 7.64 (br d, 7=7.6 Hz, 1Н), 6.77 (d, 7=1.8 Hz, 1Н), 5.42 (s, 2Н), 3.59 (t, 7=6.7 Hz, 1Н), 2.03 - 1.94 (br, 2Н), 1.84 (m, 2Н); four protons are not visible, probably due to water/water suppression overlap. 529 n ₃ s nh ₂ o y _n A<n Anh f Γ N—' «vU hn' j 336.1 1.07 5 8.50 (s, 1Н), 8.05 (d,7=8.2 Hz, 1Н), 7.88 (s, 1Н), 7.72 (br dd, 7=5.0, 3.4 Hz, 1Н), 7.64 7.58 (br, 1Н), 6.77 (s, 1Н), 5.12 (s, 2Н), 3.24 -3.10 (br, 2Н), 1.08 (t, 7=7.2 Hz, ZN) 530 QQ "i H ₃ C s€„ Λ". J-nh ^ch ' 1 JL ^N — ^f JJ hn' J 386.3 0.88 5 8.50 (s, 1Н), 8.10 (d, 7=8.2 Hz, 1Н), 7.88 (s, 1Н), 7.72 (br s, 1Н), 7.63 (br d, 7=7.3 Hz, 1Н), 6.76 ( d, 7=2.1 Hz, 1Н), 4.50 -4.35 (br, 2Н), 4.023.92 (br, 1Н), 2.66 (s, ZN), 1.19 (d, 7=6.7 Hz, ZN) 531 QQ T ^! "L s- _c „ Lm ^CHl 1 JL ^N -' JJ hn' J 386.0 0.87 5 8.50 (s, 1Н), 8.10 (d, 7=8.2 Hz, 1Н), 7.88 (s, 1Н), 7.72 (br s, 1Н), 7.63 (br d, 7=7.3 Hz, 1Н), 6.76 ( d, 7=2.1 Hz, 1Н), 4.50 -4.35 (br, 2Н), 4.023.92 (br, 1Н), 2.66 (s, ZN), 1.19 (d, 7=6.7 Hz, ZN) 532 nh _{2 o} nA^n An p 1 TN—''hn' j 377.9 1.09 5 8.92 (s, 1H), 8.18 (d,7=8.2Hz, 1H), 8.15 (brd,7=4.0Hz, 1H), 7.93 (brd,7=8.2Hz, 1H), 7.88 (brs, 1H) , 6.83 (br d, 7=0.6 Hz, 1H), 5.68 (s, 2H), 3.72 (brd, 7=4.6 Hz, 2H), 3.67 - 3.62 (br, 2H), 3.60 (br, 2H), 3.51 (w, 2H) 533 nh _{2 o} A ⁿ , ^h 1 L n—' /—\ ° ^ην Ά 377.9 1.02 5 8.71 (br d, 7=6.7 Hz, 1Н), 8.50 (s, 1Н), 8.06 (d, 7=8.2 Hz, 1Н), 7.88 (s, 1Н), 7.64 (br d, 7=4.6 Hz, 1Н), 6.77 (s, 1Н), 5.14 (s, 2Н), 4.29 (br s, IH), 3.89-3.81 (m, IH), 3.77 (dd, 7=9.0, 6.0 Hz, 1H), 2.14

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(m, 1H), 1.80 (brd, 7=4.9 Hz, 1H); two protons are not visible, probably due to water suppression/water overlap. 534 H ₃ C o X _{sn ν} Α^ν Κνη ³ 1 1 N—' nJCj HN J 350.2 1.12 5 8.52 (s, 1Н), 8.31 (brd, 7=7.3 Hz, 1Н), 8.06 (d, 7=7.9 Hz, 1Н), 7.89 (s, 1Н), 7.64 (br d, 7=1.2 Hz, 1Н ), 6.77 (s, 1H), 5.11 (s, 2H), 3.94-3.83 (br, 1H), 1.14 (s, 3H), 1.12 (s, 3H) 535 H ₃ C nh ₂ /ML njC>HN'Jj 336.1 0.99 5 8.88 (s, 1Н), 8.19 (d, 7=8.2 Hz, 1Н), 8.07 (s, 1Н), 7.97 (br d, 7=4.3 Hz, 1Н), 7.94 - 7.89 (br, 1Н), 7.83 (d, 7=1.5 Hz, 1H), 6.83 (d, 7=2.1 Hz, 1H), 4.68 (brt, 7=6.4 Hz, 2H), 2.83 (brt, 7=6.4 Hz, 2H), 2.56(s , ZN) 536 NH ₂ 0 [lY^ ^main h hn' J 366.3 1.08 5 8.96 (s, 1H), 8.57 (brt, 7=5.5 Hz, 1H), 8.19 (brd, 7=8.2 Hz, 1H), 8.13 (brs, 1H), 7.93 (brd, 7=7.0 Hz, 1H) , 7.88 (brd, 7=2.1 Hz, 1H), 6.83 (s, 1H), 5.29 (s, 2H); seven protons are not visible, probably due to water suppression/water overlap. 537 nh _{2 o} Vnh oh 1 i N— U\ Af H ₃ C sn ₃ Nχ/M hn' J 380.0 1.01 5 8.94 (s, 1Н), 8.20 (d, 7=8.2 Hz, 1Н), 8.13 (brs, 1Н), 7.99 (s, 1Н), 7.93 (br d, 7=8.2 Hz, 1Н), 7.87 (brs , 1Н), 6.83 (s, 1Н), 5.24 (s, 2Н), 1.24 (s, 6Н); two protons are not visible, probably due to water suppression/water overlap. 538 NH ₂ o V NH F 1 1 n— '—\ nJU ^f hn' J 372.0 1.04 5 8.77 (brt, 7=5.6 Hz, 1Н), 8.55 (s, 1Н), 8.07 (d, 7=8.1 Hz, 1Н), 7.90 (s, 1Н), 7.73 (br s, 1Н), 7.65 (br d, 7=7.3 Hz, 1H), 6.77 (d, 7=1.8 Hz, 1H), 6.28 -5.92 (br, 1H), 5.26 (s, 2H), 3.69 -3.50 (br, 2H) 539 z-0 ^ ^Η 2 H ₃ c uU /PLAC nJlj hn' J 406.3 0.89 5 8.43 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.72 (br s, 1H), 7.63 (brd, 7=7.8 Hz, 1H), 6.76 (s , 1Н), 4.68 - 4.55 (br, 1Н), 4.41 (brdd, 7=13.0, 5.7 Hz, 1Н), 3.66 -3.54 (br, 1Н), 1.12 (brd, 7=6.7 Hz,

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ZN); eight protons are not visible, probably due to water suppression/water overlap. 540 nh ₂ o /O. 'CN nJU HN J 387.0 1.07 δ 8.93 (s, 1H), 8.17 (d, 7=8.3 Hz, 1H), 8.13 (brd,7=1.3 Hz, 1H), 7.93 (brd,7=8.5 Hz, 1H), 7.87 (brs, 1H) , 6.83 (s, 1H), 5.73 -5.43 (m, 2H), 4.06 -3.87 (m, 1H), 3.83-3.59 (m, 2H), 3.55 - 3.43 (m, 1H), 2.44 - 2.07 (m, 3H) 541 nh ₂ о A ^NH 2 7 Г HN ^Z Ύ 308.0 0.95 δ 8.93 (brd,7=1.3Hz, 1H), 8.19 (dd, 7=8.1, 1.9Hz, 1H), 8.11 (brd, 7=1.0Hz, 1H), 7.93 (brd, 7=7.0Hz, 1H) , 7.90-7.79 (m, 2H), 7.51 (br s, 1H), 6.84 (br s, 1H), 5.24 (br s, 2H) 542 0 ^H 2 o ch ₃ AUy ^OCH 3 mAU hn' J 380.3 1.06 δ 8.91 (s, 1H), 8.18 (brd, 7=8.2 Hz, 1H), 8.14 (brs, 1H), 7.93 (brd, 7=7.9 Hz, 1H), 7.88 (brs, 1H), 6.83 (s, 1H), 5.64 (d, 7=13.7 Hz, 2H), 3.62 (br dd, 7=15.7, 4.7 Hz, 2H), 3.54 -3.42 (m, 2H), 3.15 (s, 3H), 2.93 (s, 3H) 543 nh _{2 o} nAa A ⁿ \Z ^f f 1 N—' nUlj hn' J 366.3 0.83 δ 8.52 (s, 1H), 8.07 (d, 7=8.1 Hz, 1H), 7.91 (s, 1H), 7.73 (br s, 1H), 7.66 (brd,7=8.1 Hz, 1H), 6.77 (d , 7=1.8 Hz, 1H), 5.60 -5.37 (m, 1H), 5.335.19 (m, 2H), 4.72-4.52 (m, 1H), 4.46-4.21 (m, 2H), 4.12 -3.94(m , 1H) 544 nh ₂ o yA _N Aa V NH 1 L ^N — ^f nAj hn' T 378.1 1.01 δ 8.71 (d, 7=6.7 Hz, 1H), 8.53 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.65 (brd , 7=7.9 Hz, 1H), 6.77 (d, 7=2.1 Hz, 1H), 5.14 (s, 2H), 4.29 (br d, 7=3.1 Hz, 1H), 3.84 (d, 7=7.9 Hz, 1H), 2.24 - 2.07 (m, 1H), 1.80 (brdd,7=8.1, 3.5 Hz, 1H)); two protons are not visible, probably due to water suppression/water overlap. 545 nh _{2 of n} a^n bl 1 to ^N — nJlJ hn' j 384.3 0.91 δ 8.48 (s, 1H), 8.06 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.817.69 (m, 1H), 7.63 (brd, 7=7.3 Hz, 1H), 6.77 ( d, 7=1.8 Hz, 1H), 5.37 (s, 2H), 4.78 (br t,7=12.7 Hz, 2H), 4.43 (brt,

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7=12.5Hz, 2H) 546 νη _{2 ο} VnQ-OCH3 7 Г n—' nJJi hn' J 378.3 0.86 5 8.92 (s, 1H), 8.18 (d, 7=8.2 Hz, 1H), 8.10 (brs, 1H), 7.93 (d,7=8.1 Hz, 1H), 7.85 (brs, 1H), 6.84 (d, 7=2.3 Hz, 1H), 5.46-5.27 (m, 2H), 4.48 (br dd, 7=9.1, 6.6 Hz, 1H), 4.36 4.26 (m, 1H), 4.21-4.08 (m, 2H), 3.76 (br dd, 7=10.8, 3.5 Hz, 2H), 3.25 (s, 3H) 547 Ύ o CH ₃ Hr ^OH nQW hn' J 366.1 1.02 ) 5 8.50 (s, 1H), 8.07 (d, 7=7.9 Hz, 1H), 7.92 (br s, 1H), 7.79 - 7.60 (m, 2H), 6.78 (s, 1H), 5.63 -5.46 (m , 2H), 3.67 (m, 1H), 3.53 (m, 1H), 3.16 (s, 3H), 2.91 (s, 3H); two protons are not visible, probably due to water suppression/water overlap. 548 nh _{2 o} Vnh 1 1 ^N —'hn' J 362.1 0.97 5 8.69 (brd, 7=7.6 Hz, 1Н), 8.49 (s, 1Н), 8.05 (d, 7=8.1 Hz, 1Н), 7.88 (s, 1Н), 7.72 (br s, 1Н), 7.63 (brd , 7=8.2 Hz, 1Н), 6.76 (d, 7=1.9 Hz, 1Н), 5.09 (s, 2Н), 4.22 (br d, 7=7.8 Hz, 1Н), 2.26 -2.14 (br, 2Н), 2.02- 1.92 (w, 2H), 1.741.56 (w, 2H) 549 co Ι^Λ x A° z Z ^Z Q Chu z T 392.1 1.08 5 8.90 (s, 1H), 8.18 (d,7=8.2 Hz, 1H), 8.13 (brs, 1H), 7.93 (brd,7=7.6 Hz, 1H), 7.86 (br s, 1H), 6.83 (d ,7=1.8 Hz, 1H), 5.74 (br d, 7=5.2 Hz, 1H), 5.61 (s, 2H), 5.16-5.01 (m, 1H), 4.80 - 4.66 (t, 1H), 4.08 -3.92 (t, 1H), 3.863.52 (t, 3H), 3.03 (s, 3H), 2.41-2.27 (t, 1H), 2.15 (br dd, 7=7.9, 4.6 Hz, 1H), 2.03 1.75 (t , 2H) 550 Zo nh ₂ o /ChE _n A^n Vnh Ϊ Г N—' Aj HN J 406.1 1.09 5 8.53 (s, 1H), 8.39 (t, 7=6.0 Hz, 1H), 8.06 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (brd, 7=0.6 Hz, 1H) , 7.65 (d, 7=7.6 Hz, 1H), 6.77 (d, 7=1.8 Hz, 1H), 5.15 (s, 2H), 3.84 (br dd, 7=11.3, 3.1 Hz, 2H), 3.26 (br t, 7=11.0 Hz, 2H), 3.04 (t,

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7=6.3Hz, 2H), 1.69(brs, 1H), 1.58(brd, 7=12.8Hz, 2H), 1.17(qd, 7=12.3,4.3Hz, 2H) 551 nh ₂ hn' J 290.3 1.11 5 9.11 -9.02 (m, 1H), 8.22 (d, 7=8.2 Hz, 1H), 8.11 (brs, 1H), 7.94 (brd, 7=8.2 Hz, 1H), 7.86 (brs, 1H), 6.84 ( d, 7=1.9 Hz, 1H), 5.95 (s, 2H) 552 nh _{2 o} Vn n-ch ₃ 1 I ^N —''— nULA hn' J 391.1 0.85 5 8.44 (s, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.63 (br d, 7=7.9 Hz, 1H), 6.77 ( s, 1H), 5.54 (s, 2H), 2.42 (br s, 2H), 2.32 (br s, 2H), 1.92 (s, 3H); four protons are not visible, probably due to water/water suppression overlap. 553 U ^H 2 0 CH ₃ n JM 1 L , ^N ^ ^sn z ^N 336.3 1.07 5 8.56 (d, J=2.4 Hz, 1H), 8.44 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.85 (d, 1=2.1 Hz, 1H), 7.78 - 7.73 (m, 1H), 7.66 (dd, 1=8.5,2.1 Hz, 1H), 6.55 (d, 1=2.1 Hz, 1H), 5.49 (s, 2H), 3.11 (s, 3H), 2.92 - 2.88 (t, 3H ) 554 CO O^T zz J ^s vQ> O 322.2 0.99 5 8.95 (s, 1H), 8.62 (brd, 7=2.4 Hz, 1H), 8.39 - 8.33 (t, 1H), 8.24 (d, 7=8.6 Hz, 1H), 8.16 (d,7=1.3 Hz, 1Н), 7.95 (dd, 7=8.7, 1.9 Hz, 1Н), 7.85 (d, 7=1.5 Hz, 1Н), 6.68-6.61 (t, 1Н), 5.24 (s, 2Н), 2.67 (d, 7 =4.6 Hz, ZN) 555 NH ₂ 0 Vnh ₂ 1 A / ^N - jpy ^N ^N^ 308.2 0.94 5 8.93 (s, 1H), 8.61 (brs, 1H), 8.24 (d, 7=8.6 Hz, 1H), 8.15 (s, 1H), 7.95 (dd, 7=8.7, 1.7 Hz, 1H), 7.89- 7.81 (t, 2H), 7.50 (brs, 1H), 6.68-6.59 (t, 1H), 5.24 (s, 2H) 556 0 z Qc \/I )-----( bJ About X 1 o I ω 336.2 0.81 5 8.91 (s, 1Н), 8.62 (d, 7=2.3 Hz, 1Н), 8.24 (d, 7=8.6 Hz, 1Н), 8.15 (d, 7=1.7 Hz, 1Н), 7.96 (br d, 7 =8.7 Hz, 2H), 7.85 (d, 7=0.9 Hz, 1H), 6.64 (s, 1H), 4.70 (brt, 7=6.3 Hz, 2H), 2.82 (brt, 7=6.3 Hz, 2H), 2.57 - 2.55 (t, SN)

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557 nh ₂ nA\ W ^CN 1 N^ 304.1 1.13 5 9.01 (s, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.26 (d, J=8.5 Hz, 1H), 8.16 (d, J=1.5 Hz, 1H), 7.97 (dd, J= 8.7, 1.7Hz, 1H), 7.86(d, 1=1.5Hz, 1H), 6.64(t, 1=1.8Hz, lH), 4.84(t, J=6.3Hz, 2H); two protons are not visible, probably due to water suppression/water overlap. 558 CM 4 i 322.0 0.99 5 8.91 (s, 1H), 8.62 (d, 7=2.3 Hz, 1H), 8.26 - 8.22 (m, 1H), 8.14 (d, 7=1.7 Hz, 1H), 7.95 (dd, 7=8.7, 1.8 Hz, 1H), 7.85 (d, 7=1.3 Hz, 1H), 7.49 (brs, 1H), 6.98 (brs, 1H), 6.656.61 (br, 1H), 4.67 (brt, 7=6.4 Hz, 2H ), 2.82 (brt, 7=6.4 Hz, 2H) 559 Y CN Ϊ /j ^N 332.2 1.19 5 8.94 - 8.89 (m, 1H), 8.648.59 (m, 1H), 8.26 (d, 7=8.6 Hz, 1H), 8.15 (brs, 1H), 7.95 (brd, 7=8.7 Hz, 1H), 7.87 7.83 (t, 1H), 6.67 - 6.60 (t, 1H), 4.55 (brt, 7=6.5 Hz, 2H), 2.62 - 2.55 (t, 2H), 2.03 (quin, 7=7.3 Hz, 2H), 1.661.55 (t, 2H) 560 Y o ch ₃ YY η Λγ ^{ν sz} N^W^ M 336.1 1.03 5 9.09 (s, 1H), 8.45 - 8.37 (t, 1H), 8.17 (d, 7=8.2 Hz, 1H), 8.13-8.05 (t, 1H), 7.91 (br d, 7=8.9 Hz, 1H) , 7.88 - 7.79 (t, 1H), 6.81 (d, 7=1.8 Hz, 1H), 5.40 (q, 7=7.2 Hz, 1H), 2.65 (d, 7=4.6 Hz, 2H), 1.76 (d, 7=7.0 Hz, ZN) 561 Y 0 CH ₃ n^ww ⁿ ^ 1 JI ^N \ ^CH3 AY' CH ₃ ^H N-HW M 350.1 1.11 5 8.70 (s, 1H), 8.07 (d,7=8.2 Hz, 1H), 7.90 (br s, 1H), 7.80 -7.69 (t, 1H), 7.68 -7.61 (t, 1H), 6.76 (d, 7=1.8 Hz, 1H), 5.97 -5.89 (t, 1H), 3.14 (s, ZN), 2.88 (s, ZN), 1.70 (d, 7=7.0 Hz, ZN) 562 nh ₂ o Yy h YJ ^{N SNz} nW 376.1 1.25 5 9.08 (s, 1H), 8.82 (brd, 7=7.5 Hz, 1H), 8.17 (d, 7=8.2 Hz, 1H), 8.10 (brs, 1H), 7.91 (brd, 7=8.4 Hz, 1H) , 7.84 (br s, 1H), 6.81 (s, 1H), 5.35 (q, 7=7.3 Hz, 1H), 4.24 -4.12 (t, 1H), 2.25 -2.11 (t, 2H), 2.00 - 1.86 ( t, 2Н), 1.75 (d, 7=7.1 Hz, ZN), 1.70 - 1.57 (t, 2Н)

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563 nh ₂ O _h r~O Anh 1 £ ^N \ ch ₃ H yy 413.3 1.01 δ 9.71 -9.59 (m, 1H), 9.199.05 (m, 2H), 9.00 - 8.85 (m, 1H), 8.53 (brd, 7=4.7 Hz, 1H), 8.20 (d, 7=8.2 Hz, 1H ), 8.09 (s, 1H), 7.94 (dd, 7=8.2, 1.1Hz, 1H), 7.86 - 7.76 (m, 2H), 7.38 (d, 7=7.6 Hz, 1H), 7.35 - 7.30 (m, 1H), 6.82 (d, 7=2.1 Hz, 1H), 5.62 -5.52 (m, 1H), 4.45 (d, 7=5.9 Hz, 2H), 1.83 (d, 7=7.0 Hz, ZN) 564 nh _{2 o} )-OCH ₃ 1 I ^N —\ '—' CH ₃ ^{H N} Άχ^ yj 420.1 1.21 δ 8.67 (brd, 7=4.2Hz, 1H), 8.06 (d, 7=8.1Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.65 (brd,7=7.6Hz, 1H ), 6.76 (d, 7=1.9 Hz, 1H), 5.98 (q, 7=6.8 Hz, 1H), 3.91 - 3.72 (m, 2H), 3.69 -3.53 (m, 1H), 3.433.31 (m, 1H), 3.28-3.18 (m, 3H), 3.15 -3.06 (m, 1H), 1.86 - 1.78 (m, 1H), 1.77 - 1.71 (m, 1H), 1.69 (brdd, 7=6.4, 3.9 Hz, ZN), 1.52-1.11 (m, 2H) 565 nh ₂ O Anh n 1 L l * ^- \ CH ₃ ^H ί I 413.3 0.95 Ή NMR (500 MHz, DMSOd ₆ ) δ 9.02-8.91 (m, 1H), 8.72 (s, 1H), 8.56 - 8.39 (m, 2H), 8.08 (d, 7=8.2 Hz, 1H), 7.98 7.83 ( m, 1H), 7.80 -7.57 (m, 3H), 7.34 (dd, 7=7.7, 4.9 Hz, 1H), 6.77 (s, 1H), 5.42 (q, 7=7.1 Hz, 1H), 4.36 (br d, 7=5.7 Hz, 2H), 1.78 (brd, 7=7.0 Hz, ZN) 566 NH ₂ O /--/ \E AA H jj ^{N CH3} 419.9 1.12 δ 9.01 (brs, 1H), 8.50 (brt, 7=5.6Hz, 1H), 8.13 (d, 7=8.2Hz, 1H), 8.06 (brd,7=1.8Hz, 1H), 7.93 - 7.77 (m, 2H), 6.80 (s, 1H), 5.42 (q, 7=7.0 Hz, 1H), 3.82 (br d, 7=10.7 Hz, 2H), 3.24 (brt, 7=11.3 Hz, 1H), 3.10-2.97 (m, 2H), 1.76 (d, 7=7.0 Hz, ZH), 1.72-1.61 (m, 1H), 1.55 (brd,7=13.1 Hz, 2H), 1.21-1.09 (m, 2H); one proton from the side chain is not visible, probably due to overlap with the suppressed water peak.

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567 Z SA _g G 'ζ Α ζθ ο 386.0 1.15 δ 9.10 (s, 1H), 8.92 (brt, 7=6.0Hz, 1H), 8.17 (d, 7=8.1Hz, 1H), 8.10 (brs, 1H), 7.91 (brd,7=7.7Hz, 1H) , 7.887.81 (m, 1H), 6.81 (s, 1H), 6.20-5.91 (m, 1H), 5.52 (q, 7=7.2 Hz, 1H), 3.64-3.39 (m, 2H), 1.79 (d , 7=7.1 Hz, ZN) 568 he νη ₂ o y Η Cj ^{Ν SNz} μ 366.3 1.01 δ 8.67 (s, 1H), 8.42 (t, 7=5.6 Hz, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.77 - 7.67 (m, 1H), 7.66 - 7.58 (m, 1H), 6.75 (d, 7=1.8 Hz, 1H), 5.37 (q, 7=7.2 Hz, 1H), 3.23 -3.11 (m, 2H), 1.73 (d, 7=7.0 Hz, ZN ); two protons are not visible, probably due to overlap with the suppressed water peak. 569 H ₃ C ΝΗ ₂ o \_ SN ₃ du Α / Α SNz Η Η Τ ³ Μ 364.1 1.19 δ 8.82 (brs, 1H), 8.40 (brd, 7=7.5 Hz, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.95 (br s, 1H), 7.80 -7.67 (m, 2H), 6.77 (d, 7=1.7Hz, 1H), 5.32 (q, 7=7.2Hz, 1H), 3.84 (dq, 7=13.5, 6.5Hz, 1H), 1.73 (d, 7=7.1Hz, ZN), 1.10 (dd, 7=12.2, 6.6Hz, 6H) 570 ΝΗ ₂ 0 iWv AU SNz ⁿ n^AA Μ 392.3 1.11 δ 9.10 (s, 1H), 8.17 (d, 7=8.2 Hz, 1H), 8.10 (brs, 1H), 7.91 (q, 7=7.9 Hz, 1H), 7.85 (brs, 1H), 6.81 (d, 7=1.8 Hz, 1H), 6.09-6.01 (m, 1H), 3.783.44 (m, 5H), 1.75 (d, 7=7.0 Hz, ZN); three protons are not visible, probably due to overlap with the suppressed water peak. 571 Q ^Z AND -A zO cr γ z ABOUT CM )-----( Aq IZ'z 412.1 1.31 δ 8.90 (brt, 7=6.0 Hz, 1H), 8.74 (s, 1H), 8.09 (d, 7=8.2 Hz, 1H), 7.91 (s, 1H), 7.73 (br d, 7=2.1 Hz, 1H ), 7.67 (br d, 7=6.4 Hz, 1H), 7.36 -7.21 (br, 5H), 6.77 (d, 7=1.8 Hz, 1H), 5.43 (q,7=6.9 Hz, 1H), 4.34 ( brd,7=6.1Hz, 2H), 1.79 (d, 7=7.0Hz, ZN) 572 HO nh ₂ 0 D yy AU CH ₃ nJU ⁿ u 380.1 1.03 δ 8.65 (s, 1H), 8.38 (brt, 7=5.5 Hz, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.74 7.67 (m, 1H), 7.63 (br d, 7=8.2 Hz, 1H), 6.75 (d, 7=2.1 Hz, 1H), 5.30 (q, 7=6.8 Hz, 1H), 3.41 (t, 7=6.3 Hz, 2H), 3.14 (qt, 7=13.7, 6.5Hz, 2H),

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1.73 (d, 7=7.0 Hz, ZN), 1.63 - 1.49 (m, 2H) 573 sn ₃ < sn ₃ N—' nh _{2 0} XX n K} ^{N SNz N} U 421.1 1.00 δ 8.75 (s, 1H), 8.47 - 8.33 (m, 1H), 8.07 (d, 7=7.9 Hz, 1H), 7.92 (s, 1H), 7.78 - 7.63 (m, 2H), 6.76 (d, 7 =1.8 Hz, 1H), 5.43-5.31 (m, 1H), 2.75 (br s, 4H), 1.75 (br d, 7=7.0 Hz, 3H), 1.01 (brt, 7=7.0 Hz, 6H); four protons are not visible, probably due to overlap with the suppressed water peak. 574 T CO -O A ABOUT ? ” CO X T M Z s. oh kuu IZ 2 z 394.3 0.90 δ 9.08 (s, 1H), 8.17 (d, 7=7.9 Hz, 1H), 8.13 - 8.07 (m, 1H), 8.05 (s, 1H), 7.96 - 7.78 (m, 2H), 6.81 (brd,7 =0.6 Hz, 1H), 5.45 (q, 7=7.2 Hz, 1H), 1.73 (d, 7=7.0 Hz, 3H), 1.21 (s, 6H); two protons are not visible, probably due to overlap with the suppressed water peak. 575 ζ^ \ ^ZJ ~ MX \ / Z ) ( yu zK 'ζ X .O ο yes ζ 1 ω _Ζ υ ο yu 440.1 1.05 δ 8.73 (s, 1H), 8.07 (d, 7=7.9 Hz, 1H), 7.92 (s, 1H), 7.73 (br s, 1H), 7.70 - 7.64 (m, 1H), 6.77 (d, 7= 2.1Hz, 1H), 6.146.05 (m, 1H), 3.45 -3.32 (m, 2H), 3.25 -3.03 (m, 4H), 2.90 -2.86 (m, 1H), 2.82-2.77 (m, 1H) , 1.74 (d, 7=7.0 Hz, 3H) 576 νη ₂ 0 . "X® Η Γ] ^{Ν SNz} νΑα Μ 362.2 1.08 δ 8.69 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.66 (br d, 7=7.9 Hz, 1H), 6.76 ( d, 7=1.8 Hz, 1H), 5.46 (q, 7=7.1 Hz, 1H), 4.35 4.25 (m, 1H), 4.21 -4.09 (m, 1H), 3.96 -3.86 (m, 2H), 2.26 - 2.17(m, 2H), 1.69(d, 7=7.0Hz, 3H) 577 νη ₂ 0 ΑΧ SNz Η nAA Μ 397.9 1.17 δ 9.06 (s, 1H), 8.18 (d, 7=8.2 Hz, 1H), 8.09 (brs, 1H), 7.96 -7.87 (m, 1H), 7.87-7.77 (m, 1H), 6.86 - 6.80 (m , 1H), 5.65 (q, 7=7.0 Hz, 1H), 4.92 4.78 (m, 1H), 4.73 - 4.62 (m, 1H), 4.50 -4.33 (m, 2H), 1.76 (d, 7=7.0 Hz , 3H)

- 199 042018

578 ΝΗ ₂ η 1 JL n—\ ΓγΝ CH ₃ aUU ^N U 392.1 1.06 5 9.09 (s, IH), 8.18 (t, 7=7.8 Hz, IH), 8.14-8.06 (m, IH), 7.92 (brd, 7=8.2 Hz, IH), 7.86 (brs, IH), 6.82 ( d, 7=1.5 Hz, IH), 5.63 - 5.55 (m, IH), 4.22-4.17 (m, IH), 4.15 (s, IH), 4.01 (brd,7=8.9 Hz, IH), 3.83 -3.71 (m, 2H), 1.73 (t, 7=6.7 Hz, SA), 1.39 (d, 7=16.5 Hz, SA) 579 nh ₂ ° z\ f Г N—( Aan ch ₃ H 1 nAA M 378.1 1.02 δ 9.10 (d, 7=1.8 Hz, IH), 8.24 -8.16(m, IH), 8.12 (br s, IH), 7.92 (brd,7=7.6 Hz, IH), 7.90 - 7.79 (m, IH) , 6.81 (s, IH), 5.64-5.51 (m, IH), 4.58-4.40 (m, 2H), 4.174.10 (m, IH), 4.10-3.89 (m, IH), 3.72-3.59 (m, IH), 1.72 (t, 7=6.9 Hz, ZN) 580 NH _{2 o} ^cn LuU AAn ch ₃ <j 401.0 1.12 δ 9.08 (brs, IH), 8.22-8.14 (m, IH), 8.10 (brs, IH), 7.95 -7.78 (m, 2H), 6.81 (brs, IH), 5.82 (brt, 7=6.5 Hz, IH), 4.07 -3.37 (m, 4H), 2.41 -2.33 (m, IH), 2.31 -2.19 (m, IH), 2.18-2.07 (m, IH), 1.80-1.71 (m, 3H) 581 OCH ₃ nh _{2 o ν} Αλ > ^nh 1 £ ^N \ Ar ^N ' CH ₃ H 1 yj 380.2 1.05 δ 8.78 (s, IH), 8.52 (brt, 7=5.3 Hz, IH), 8.09 (d, 7=8.2 Hz, IH), 7.93 (br s, IH), 7.76 -7.68 (m, 2H), 6.77 (d, 7=1.8 Hz, IH), 5.42 - 5.33 (m, IH), 3.41-3.33 (m, 2H), 3.293.24 (m, 2H), 3.24-3.20 (m, 3H), 1.73 (d , 7=7.3 Hz, ZN) 582 OCH ₃ nh ₂ o JH 1 L - ^N \ ^SNz Af ^N ' CH ₃ and h T nAA AJ 394.3 1.17 Ή NMR (500 MHz, DMSOd ₆ )6 8.69(br d, 7=5.9 Hz, IH), 8.06 (d, 7=8.2 Hz, IH), 7.89 (brs, IH), 7.72 (br s, IH), 7.65 (brd,7=8.1 Hz, IH), 6.76 (s, IH), 6.02-5.87 (m, IH), 3.31 (s, IH), 3.22 (s, IH), 3.13 (s, IH), 2.89 (s, 2H), 1.70 (t, 7=6.6 Hz, ZN); five protons are not visible, probably due to overlap with suppressed water peak or low degree of integration.

- 200 042018

583 co co T r About Q z O IZ 'z 378.1 1.39 5 8.69 (s, 1H), 8.06 (d, 7=7.9 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.65 (br d, 7=7.9 Hz, 1H), 6.75 ( d, 7=1.8 Hz, 1H), 5.84 (q, 7=6.7 Hz, 1H), 3.41 3.32 (m, 1H), 3.27-3.19 (m, 1H), 1.70 (d, 7=6.7 Hz, ZN) , 1.14 (t, 7=7.0 Hz, ZN), 1.03 (t, J=7.0 Hz, ZN); two protons are not visible, probably due to overlap with the suppressed water peak. 584 HOX H ₃ CN ZyN CH ₃ ^H ί J Μ 380.3 1.06 5 9.20 - 9.06 (br, 1Н), 8.27 8.06 (br, 2Н), 8.00 - 7.80 (br, 2Н), 6.89 - 6.74 (br, 1Н), 6.12 -5.95 (br, 1Н), 3.81 -3.59 (br , 1H), 3.84–3.38 (w, 4H), 1.82–1.70 (w, 3H); six protons are not visible, probably due to water suppression/water overlap. 585 νη ₂ ΑΧν '— _h 0 0 th ΚΙ ^ΗΝ “\ ^Ν Μ < 0CH ₃ 430.3 1.12 5 8.48 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.63 (brd,7=7.8 Hz, 1H), 6.75 (d , 7=1.9 Hz, 1Н), 4.46 (brt, 7=6.7 Hz, 2Н), 3.73 -3.61(br, ZN), 3.28 (brt, 7=6.2 Hz, 2Н), 3.22 (s, ZN), 2.98 (br d, 7=1.8 Hz, 2H), 2.16-2.08 (br, 2H) 586 νη ₂ ϊ lX η ίΎ ^Ν< Ν JLZ HN-S' ^N bj]^ ^CH3 386.3 1.03 5 8.47 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.87 (d, 7=0.9 Hz, 1H), 7.71 (brs, 1H), 7.62 (br d, 7=8.2 Hz, 1H ), 6.75 (d, 7=1.8 Hz, 1H), 4.48 (t, 7=6.9 Hz, 2H), 3.00 (brd, 7=5.2 Hz, 2H), 2.91(s, 3H), 2.13 (quin, 7 =6.9Hz, 2H) 587 νη ₂ ϊ jF' aX ^N ' X^ b 448.2 1.10 5 8.42 (s, 1Н), 8.04 (d, 7=7.9 Hz, 1Н), 7.87 (s, 1Н), 7.77 (d, 7=7.3 Hz, 2Н), 7.71 (br s, 1Н), 7.61 (brt , 7=6.9 Hz, 2H), 7.58 -7.51 (m, 2H), 6.75 (d, 7=2.1 Hz, 1H), 4.42 (brt, 7=6.7 Hz, 2H), 2.80 (brt, 7=6.6 Hz , 2Н), 2.05 (quin, 7=6.9 Hz, 2Н) 588 νη ₂ ϊ ιΧ Η ίΧτ^ '% ⁰ JJ ^ΗΝ Λ ν' Υ )—CH3 'M H ₃ C 414.2 1.12 5 8.47 (s, 1H), 8.06 (d, 7=8.2 Hz, 1H), 7.87 (d, 7=1.4 Hz, 1H), 7.71 (brs, 1H), 7.62 (br d, 7=8.5 Hz, 1H ), 6.75 (d, 7=2.1 Hz, 1H), 4.47 (t, 7=6.9 Hz, 2H), 3.23 -3.12 (br, 1H),

- 201 042018

3.01 (q, 7=6.3Hz, 2H), 2.12 (quin, 7=7.0Hz, 2H), 1.22 (d, 7=6.7Hz, 6H) 589 4 o'Y z. CM )-----( 'Αχ iz&z 412.2 1.17 5 8.47 (s, 1H), 8.07 (d, 7=8.1 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.62 (brd,7=7.8 Hz, 1H), 6.75 (d , 7=1.9Hz, 1H), 4.49 (brt, 7=6.9Hz, 2H), 3.04 (brd,7=5.5Hz, 2H), 2.15 (quin, 7=6.6Hz, 2H), 1.89 (s, ~ 2H), 0.98 - 0.89 (m, 2H), 0.90-0.81 (m, 2H) (one methine hidden by solvent) 590 nh ₂ q, <p XX Ά 'st /4An >-7 Η HT Η V nXa M 398.3 1.13 δ 8.50 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H), 7.78 7.67 (m, 1H), 7.63 (br d, 7=7.0 Hz, 1H), 6.75 ( d, 7=1.5 Hz, 1H), 4.51 (t, 7=5.6 Hz, 2H), 3.55 (brd, 7=4.3 Hz, 1H( intensity reduced by water suppression), 0.96 - 0.85 (br, 4H) 591 0 °χ ^Ζ £ V-° 1 o co z T o CM ) ( ¹ xq ΣZ 'z 420.3 1.21 δ 8.49 (s, 1H), 8.04 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.78 7.67 (m, 1H), 7.62 (br d, 7=8.3 Hz, 1H), 6.75 ( d, 7=2.0 Hz, 1H), 4.63 (s, 2H), 3.64 (s, 4H), 3.59 -3.37 (m, 3H) (intensity decreases due to water suppression), 1.29 (s, 6H) 592 £ δ °z CO Χί^Ο 0-7 About I T z o 4-Q IZ& Z 378.3 1.24 δ 8.63 (brs, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.92 (s, 1H), 7.74 (br s, 1H), 7.69 (br d, 7=8.2 Hz, 1H), 6.76 ( s, 1H), 4.64 (s, 2H), 1.30 (s, 6H) (some resonances are hidden by water suppression) 593 N ^H2 _H I rA AAn' ⁰ o ^H nJ 443.3 1.11 δ 8.51 (s, 1H), 8.08 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H), 7.71 (br s, 1H), 7.64 (brd, 7=8.2 Hz, 1H), 6.76 (s , 1H), 4.49 (brt, 7=5.8 Hz, 2H), 3.53 (br s, 1H) (intensity is reduced by water suppression), 2.92 (br s, 4H) (some resonances are hidden by water suppression) 594 z \ ' ^zz ty oh ^{? %} ZI \ po JI ^ω ZI O T 394.3 1.06 δ 8.77 - 8.50 (m, 1H), 8.12 (d, 7=8.2 Hz, 1H), 7.98 (br s, 1H), 7.82 - 7.73 (m, 1H), 7.65 (brt, 7=5.3 Hz, 1H) , 6.78 (s, 1H), 4.56 (s, 2H), 3.51 -3.33

- 202 042018

(m, 1H) (intensity decreases due to water suppression), 3.16 (q, 7=6.3 Hz, 1H) (intensity decreases due to water suppression), 1.18 (s, 6H) 595 nh ₂ l33l NJJ HN—S ⁱ⁰ β 449.0 1.13 5 8.94 (d, 7=1.8 Hz, 1H), 8.88 (s, 1H), 8.80 (d, 7=4.0 Hz, 1H), 8.16 (d, 7=8.2 Hz, 2H), 8.10 (brs, 1H) , 8.06 (brt, 7=5.0 Hz, 1H), 7.92 (br d, 7=8.2 Hz, 1H), 7.85 (br s, 1H), 7.63 (dd, 7=8.1.4.7 Hz, 1H), 6.81 ( d, 7=1.8Hz, 1H), 4.51 (brt, 7=6.9Hz, 2H), 2.89 (q, 7=6.3Hz, 2H), 2.09 (quin, 7=6.6Hz, 2H) 596 _{H r} CH ₃ Η ΐ 1 HjC. ³ _n a _f I py BP kJU DU 414.3 1.2 5 8.40 (s, 1H), 8.10 (brt, 7=5.6 Hz, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.87 (s, 1H), 7.71 (br s, 1H), 7.63 (brd , 7=8.0 Hz, 1H), 6.75 (d, 7=1.7 Hz, 1H), 6.20 -5.88 (m, 1H), 4.54 (s, 2H), 3.63 -3.34 (m, 1H) (intensity decreases due to water suppression), 1.18 (s, 6H) 597 ζ V ^ζτ Yy ₂ l ZI 1 o JI ^ω h I 406.1 1.09 5 8.49 (s, 1H), 8.11 (d, 7=8.2 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.67 (brd, 7=8.2 Hz, 1H), 6.76 (d , 7=1.8 Hz, 1H), 4.50 (s, 2H), 4.37 - 4.28 (m, 1H), 1.16 (s, 6H) (some resonances are masked by water suppression) 598 9 τζ _ co Χ^ί-Ο O-J o] τ ζ ο BP ΤΖ' 'ζ 404.1 1.27 5 8.37 (s, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.75 7.67 (m, 2H), 7.63 (br d, 7=8.2 Hz, 1H), 6.75 ( d, 7=2.1 Hz, 1H), 4.48 (s, 2H), 4.27 4.15 (m, 1H), 2.19-2.06 (m, 2H), 1.64-1.51 (m, 2H), 1.14 (s, 6H) 599 41 CO τ Γ ό) τ CO G τζ & 'ζ 426.3 1.28 5 8.88 (s, 1H), 8.15 (d, 7=8.2 Hz, 1H), 8.10 (brs, 1H), 7.91 (brd,7=8.2 Hz, 1H), 7.85 (br s, 1H), 6.82 (d , 7=2.0 Hz, 1H), 4.62 (s, 2H), 1.22 (s, 6H) (some resonances are hidden by water suppression)

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600 z ts zo / z Ο ^ω z 376.1 1.11 δ 8.53 (s, 1H), 8.07 (d, 7=7.9 Hz, 1H), 7.90 (s, 1H), 7.72 (br s, 1H), 7.65 (brd, 7=8.2 Hz, 1H), 6.75 (d , 7=1.8 Hz, 1H), 4.58 (s, 2H), 3.00 -2.75 (m, 3H), 1.91 (s, 3H), 1.09-1.01 (m, 2H), 1.01 -0.92 (m, 2H) ( some resonances are hidden by water suppression) 601 I ABOUT ) Xz . cz IZz 441.1 1.03 6 9.79-9.53 (m, 1Н), 8.86 (s, 1Н), 8.42 (br s, 2Н), 8.36 (br t, 7=5.6 Hz, 1Н), 8.13 (d, 7=8.2 Hz, 1Н), 8.09 (brs, 1H), 7.91 (brd, 7=8.2 Hz, 1H), 7.84 (brs, 1H), 7.58 (br d, 7=7.8 Hz, 1H), 7.26 (dd, 7=7.5, 5.0 Hz, 1Н), 6.82 (d, 7=1.4 Hz, 1Н), 4.62 (s, 2Н), 4.31 (brd, 7=5.9 Hz, 2Н), 1.25 (s, 6Н) 602 IZ co N^O O-J ABOUT ] Xz'Zy IZ A z 448.1 1.2 δ 8.39 (s, 1H), 8.04 (d, 7=8.1 Hz, 1H), 7.86 (s, 1H), 7.71 (br s, 1H), 7.62 (brd, 7=6.6 Hz, 2H), 6.75 (d , 7=1.6 Hz, 1H), 4.50 (s, 2H), 3.67 (br dd, 7=11.1, 2.4 Hz, 2H), 3.10 (br t,7=11.0 Hz, 2H), 2.93 (brt, 7= 6.4 Hz, 2H), 1.69 - 1.54 (m, 1H), 1.31 (brd,7=13.0 Hz, 2H), 1.19 (s, 6H), 1.07-0.95 (m, 2H) 603 Z Oy O 'and I \ /° ω-L ω 392.1 1.37 δ 8.50 (brs, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.91 (s, 1H), 7.73 (br s, 1H), 7.68 (br d, 7=7.9 Hz, 1H), 7.30 ( d, 7=7.9 Hz, 1H), 6.76 (d, 7=2.1 Hz, 1H), 4.52 (s, 2H), 4.00-3.86 (m, 1H), 1.16 (s, 6H), 1.03 (d, 7 =6.7Hz, 6H) 604 AHC CH ₃ 1 . -5 _NH2 ΑΛν o i JU Μ 350.1 1.1 δ 8.51 (s, 1H), 8.07 (d, 7=8.2 Hz, 1H), 7.90 (s, 1H), 7.73 (br s, 1H), 7.66 (brd, 7=7.2 Hz, 1H), 7.27 (s , 1H), 7.03 (s, 1H), 6.76 (d, 7=2.0 Hz, 1H), 4.52 (s, 2H), 1.17 (s, 6H) 605 NH ₂ n 1 \/ N^, U Μ ⁿ ί 1 c/ nAA AU 439.1 1.01 δ 8.61 (s, 1H), 8.49 (t, 7=6.0 Hz, 1H), 8.41 (d, 7=4.3 Hz, 1H), 8.02 (d, 7=8.2 Hz, 1H), 7.88 (s, 1H) , 7.71 (brs, 1H), 7.62 (br d, 7=7.9 Hz, 1H), 7.50-7.43 (m, 1H), 7.17 (dd, 7=7.0.5.2 Hz, 1H), 7.01 (d, 7= 7.6Hz, 1H), 6.76(d, 7=1.8Hz, 1H), 4.74(s, 2H), 4.36(d,

- 204 042018

7=5.8 Hz, 2H), 1.32 - 1.25 (m, 2H), 1.18 - 1.09 (m, 2H) 606 h Η \/I )-----(th O At 411.9 1.15 5 9.02 (s, 1H), 8.18 (d, 7=8.2 Hz, 1H), 8.09 (brs, 1H), 8.06 (brt, 7=5.8 Hz, 1H), 7.91 (br d, 7=7.9 Hz, 1H ), 7.85 (br s, 1H), 6.81 (d, 7=1.8 Hz, 1H), 6.13-5.81 (m, 1H), 4.73 (s, 2H), 1.36 - 1.25 (m, 2H), 1.22 - 1.14 (m, 2H) (some resonances are hidden by water suppression) 607 ' ^ZI t n ) ( m o > 402.3 1.02 Ή NMR (500 MHz, DMS0d ₆ ) 5 8.47 (s, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.86 (s, 1H), 7.71 (brs, 1H), 7.62 (brd, 7=7.9 Hz, 1H), 6.75 (d, 7=2.1 Hz, 1H), 4.57 (s, 2H), 3.23 (br s, 2H), 1.77 - 1.49 (m, 4H), 1.05 -0.95 (m, 4H) ( some resonances are hidden by water suppression) 608 That X z o sch) (Ay IZ p Z 362.1 1.08 5 8.75 (brs, 1H), 8.11 (d, 7=7.9 Hz, 1H), 7.95 (br s, 1H), 7.74 (brd,7=7.9 Hz, 2H), 7.65 (brd,7=4.3 Hz, 1H ), 6.77 (d, 7=1.8 Hz, 1H), 4.67 (s, 2H), 2.57 (d, 7=4.3 Hz, 3H), 1.25-1.17 (m, 2H), 1.13-1.06 (m, 2H) 609 P _n - CH ₃ Η 1 H ₃ C., JN ~ V; 4 NpyPp 0 ⁰ Η ^Ν Ρ 456.0 1.07 5 8.39 (s, 1H), 8.05 (d, 7=8.1 Hz, 1H), 7.92 (brt, 7=5.5 Hz, 1H), 7.86 (d, 7=1.3 Hz, 1H), 7.71 (brs, 1H) , 7.61 (brd, 7=8.3 Hz, 1H), 6.74 (d, 7=2.1 Hz, 1H), 4.51 (s, 2H), 3.26 (br t, 7=6.9 Hz, 2H), 2.96 (s, 3H ), 1.15 (s, 6H) (some resonances are hidden by water suppression) 610 0CH ₃ Г НзсР0 ΓΥ\Ρ4 Ar ^ν ' ^Η 1 yj 448.2 1.46 5 8.58 (s, 1Н), 8.07 (d, 7=7.9 Hz, 1H), 7.89 (s, 1H), 7.72 (br s, 1H), 7.66 (br d, 7=7.9 Hz, 1H), 6.76 ( d, 7=2.1 Hz, 1H), 4.62 (s, 2H), 3.98 - 3.85 (m, 2H), 3.28 (s, 3H), 1.55 - 1.43 (m, 2H), 1.28 (s, 6H) (some resonances are hidden by water suppression)

- 205 042018

611 AAn ⁰ \J 441.1 1.03 5 8.49-8.41 (m, 2H), 8.32 (br t, 7=5.7 Hz, 1H), 8.05 (d, 7=8.2 Hz, 1H), 7.90 (s, 1H), 7.72 (brs, 1H), 7.67 -7.61(m, 1H), 7.55(t, 7=7.7Hz, 1H), 7.24-7.16(m, 1H), 7.04(d, 7=7.9Hz, 1H), 6.76(d, 7=2.0Hz, 1H), 4.59 (s, 2H), 4.40 (d, 7=5.6 Hz, 2H), 1.27 (s, 6H) 612 γ ^Η 2 H ₃ C HN-CH ₃ 4) ij ' Ν^Λ hn' J 350.1 0.52 (400 MHz, MeOH-d4) 5 8.69 (s, 1H), 8.32 (d, 7=8.5 Hz, 1H), 8.02 (s, 1H), 7.96 (d, 7=7.9 Hz, 1H), 7.79 (s , 1H), 6.84 (s, 1H), 4.46-4.57 (m, 1H), 4.68-4.78 (m, 1H), 3.143.25 (m, 1H), 2.65 (s, 3H), 1.28 (d, 7 =6.8Hz, ZN) 613 Y ⁿ 2 H ₃ C 0 N^Y^ / \ 1 N—' N—, iJ ^N ' νΛΛ oh hn' j 392.3 1.03 5 8.42 (d, 7=8.6 Hz, 1H), 8.06-8.13 (m, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.61-7.66 (m, 1H), 6.76 (s, 1H ), 4.464.57 (m, 1H), 4.29-4.43 (m, 3H), 4.11-4.17 (m, 1H), 3.944.03 (m, 2H), 3.78-3.90 (m, 1H), 3.07-3.16 (m, 1H), 1.041.11 (m, 3H) 614 Y ⁿ 2 H ₃ C 0 N^Y*^ / \ 1 1 N—' NH A/ ^N ' J m 1 J ³ CH ₃ HN T 378.1 1.17 5 8.55 (br. s, 1H), 8.10 (d, 7=8.2 Hz, 1H), 7.95 (br. s, 1H), 8.79 (d, 7=7.6 Hz, 1H), 7.68-7.83 (m, 1H ), 6.78 (s, 1H), 4.48 (ABx, 745=13.3 Hz, 7^=9.0 Hz, 7l=5.8 Hz, Δν=91 Hz, 2H), 3.77-3.84 (br, 1H), 2.93-3.01 ( br, 1Н), 1.09 (d, 7=6.7 Hz, ZN), 1.00 (d, 7=6.4 Hz, 3H), 0.88(d, 7=6.4 Hz, ZN) 615 nh _{2 o} A _ A' P ^H 3 Ϊ ^N Au A<*N CH ₃ ^{h CH} 3 HN J 378.1 1.19 5 8.84 (s, 1Н), 8.10 (d, 7=8.2 Hz, 1Н), 7.87 (s, 1Н), 7.83 (d, 7=7.6 Hz, 1Н), 7.68-7.77 (br, 1Н), 7.63 ( br. d, 7=9.2 Hz, 1H), 6.75 (d, 7=1.8 Hz, 1H), 4.98-5.06 (br, 1H), 3.73-3.81 (br, 1H), 2.73 (ABx, 745=15.4 Hz , 7 _P =7.8 Hz, Jbx=6.2 Hz, Δν=64 Hz, 2Н), 1.60 (d, 7=6.7 Hz, ZN), 1.00 (d, 7=6.4 Hz, 3H), 0.88(d, 7= 6.7 Hz, ZN).

- 206 042018

616 p _o A Z „ Cj Chu k Z t 406.0 1.15 δ 8.53 (s, 1H), 8.09 (d,/=8.2Hz, 1H), 7.88 (d,/=1.2Hz, 1H), 7.72 (s, 1H), 7.64 (d, 7=8.3Hz, 1H) , 6.76 (d, 7=2.1 Hz, 1H), 5.05-5.14 (m, 1H), 3.05 (ABx, /<5=16.2 Hz, /<x=8.1 Hz, Jbx=5.3 Hz, Δν=161 Hz, 2H), 1.62 (d, 7=6.7 Hz, ZN); morpholine methylene units are not observed 617 nh _{2 o} i'jUΝ—\G ^CH 3 AA' CH3 A nAA ην' T 364.2 0.57 (400 MHz, MeOH-d4) δ 8.81 (s, 1H), 8.34 (d,/=8.2 Hz, 1H), 8.02 (d, 7=1.1 Hz, 1H), 7.96 (dd, J=8.3, 1.5 Hz , 1H), 7.79 (d,/=2.2 Hz, 1H), 7.85 (d,/=2.3 Hz, 1H), 5.20-5.29 (m, 1H), 3.22 (ABx,/45=16.6 Hz, /^= 9.0 Hz, /lx=4.3 Hz, Δν=174 Hz, 2H), 3.08 (s, ZN), 2.87 (s, ZN), 1.75 (d,/=6.7 Hz, ZN) 618 nh ₂ o 1 jU ^N U ' ^SNz ( nC A ^f ΗΝ'Ύ ^F 399.8 1.14 δ 8.54 (s, 1H), 8.42 (t, /=5.6 Hz, 1H), 8.10 (d, /=7.9 Hz, 1H), 7.91 (d, /=0.6 Hz, 1H), 7.74 (br. s, 1H), 7.67 (d, /=7.9 Hz, 1H), 6.77 (d, /=2.1 Hz, 1H), 5.92 (tt, /=56, 3.7 Hz, 1H), 5.03-5.12 (m, 1H), 2.89 (ABx,/45=15.0 Hz, Jax=7.6 Hz, J _B x=6A Hz, Δν=71 Hz, 2H), 1.62 (d, /=6.7 Hz, ZN); one methylene unit is missing 619 nh _{2 o} nUC Dr 1 L nA ^NH Cf ^N ' CH ₃ < ^ΗΝ ^/^ ^H °^ 394.1 1.06 δ 8.94 (s, 1H), 8.21 (d, /=8.3 Hz, 1H), 8.11 (br. s, 1H), 7.99 (t, /=6.0 Hz, 1H), 7.93 (dd, /=8.2, 2.2 Hz,, 1H), 7.86 (br. s, 1H), 6.82 (d,/=2.0 Hz, 1H), 5.11-5.18 (m, 1H), 3.26 (t,/=6.3 Hz, 2H), 3.00- 3.06 (m, 2H), 2.90-2.97 (m, 1H), 2.81 (ABx, /45=15.0 Hz, /4x=8.3 Hz, Jbx=5A Hz, Δν=52 Hz, 2Η), 1.62 (d, / =6.7 Hz, ZN); one methylene unit is not observed.

- 207 042018

620 nh _{2 0} nAA\ rA 1 kz ^N \ ^NH JAJ ^N ' ^CH3 $ ^but 380.1 1.04 5 8.93 (s, 1H), 8.22 (d, 7=8.2 Hz, 1H), 8.11 (br. s, 1H), 8.02 (t, 7=5.6 Hz, 1H), 7.94 (br. d, 7=8.9 Hz,, 1H), 7.87 (br. s, 1H), 6.83 (d, 7=1.5 Hz, 1H), 5.11-5.18 (m, 1H), 3.25-3.35 (m, 2H), 3.03-3.10 (m , 2H), 2.90-2.97 (m, 1H), 2.83 (ABx, 7gv=15.2 Hz, 7^=7.9 Hz, J _B x=5J Hz, Δν=56 Hz, 2H), 1.61 (d, 7=6.7 Hz, ZN) 621 nh ₂ o nZA \ gA 1 LN - ( HN-CH3 ^CH3 HN J 350.0 1.09 5 8.49 (s, 1H), 8.08 (d, 7=8.1 Hz, 1H), 7.91 (q, 7=4.4 Hz, 1H), 7.88 (d, 7=1.1 Hz, 1H), 7.72 (d, 7= 0.4Hz, 1H), 7.63(d, 7=8.0Hz, 1H), 6.76(d, 7=2.0Hz, 1H), 5.01-5.09(m, 1H), 2.80(ABx, 7lv=14.9Hz, Jax= 7% Hz, Jbx=6.2 Hz, Δν=77 Hz, 2H), 1.58 (d, 7=6.7 Hz, ZN); one methyl group is missing 622 nh _{2 o} N—AnO— AAn CH ₃ nAA hn' J 390.1 1.19 5 8.92 (s, 1Н), 8.23 (d, 7=7.6 Hz, 1Н), 8.20 (d, 7=8.2 Hz, 1Н), 8.07-8.15 (br, 1Н), 7.837.97 (br, 2Н), 6.82 (d, 7=0.6 Hz, 1H), 5.09-5.17 (m, 1H), 4.06-4.16 (br, 1H), 2.78 (ABx, Jab—15.3 Hz, Jax~7.9 Hz, Jbx=5Z Hz, Δν =50 Hz, 2Н), 1.99-2.07 (br, 1Н), 2.072.15 (br, 1Н), 1.77-1.85 (br, 1Н), 1.65-1.73 (br, 1Н), 1.61 (d, 7=6.7 Hz, ZN), 1.52-1.59 (m, 2Н) 623 X o /γΟ I z e. GrAq A'z X 434.1 1.25 5 8.99 (d, 7=3.4 Hz, 1H), 8.21 (d, 7=8.6 Hz, 1H), 8.11 (br. s, 1H), 7.93 (d, 7=8.5 Hz, 1H), 7.87 (br. s, 1H), 6.82 (d, 7=1.2 Hz, 1H), 5.14-5.22 (m, 1H), 3.61-3.81 (m, 2H), 2.903.09 (m, 4H), 1.76-1.84 (m, 1H), 1.66-1.73 (m, 1H), 1.64 (d, 7=6.7 Hz, ZH), 1.38-1.47 (m, 1H), 1.22-1.31 (m, 1H); one methoxy and one methine unit is not observed 624 nh ₂ o nAy\ / \ 1 1 N—I NH UJ W hn' Ύ \ / \=J 434.1 1.26 5 8.56 (s, 1H), 8.42 (t, 7=5.6 Hz, 1H), 8.10 (dd, 7=8.2, 2.1 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=0.6 Hz, 1Н), 7.66 (d, 7=8.6 Hz, 1Н), 6.77 (d, 7=1.8 Hz, 1Н), 5.92(«,7=56.3.7 Hz, 1Н), 5.05-5.13 (br, 1Н), 2.873.77 (t, integration unclear due to suppression of the water signal), 1.67-1.82 (br, 2H), 1.62 (d, 7=6.7 Hz, ZN), 1.131.45 (br, ZN)

Assessment of biological activity.

Measurement of IL-Ιβ production in PMA-differentiated THP-1 cells.

THP-1 cells were obtained from the American Type Culture Collection and subcultured according to the supplier's instructions. Prior to experiments, cells were cultured in RPMI 1640 medium containing 10% heat-inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml) and maintained in log phase until the beginning of the experiment. Before the experiment, THP-1 was processed

- 208 042018 PMA (phorbol-12-myristate-13-acetate) (10 µg/mL) was waived for 24 h. On the day of the experiment, the medium was removed and the attached cells were treated with trypsin for 2 min; -saline buffer solution), slowed rotation, resuspended in 2% heat-inactivated FBS with RPMI at a concentration of 1x10 ⁶ cells/ml and 100 μl were sown on a 96-well plate. The compounds were dissolved in dimethyl sulfoxide (DMSO) and added to the culture medium to achieve the desired concentration (eg 100, 30, 10, 3, 1, 0.3 or 0.1 μM). Cells were incubated with compounds for 4 hours. Cell-free supernatant was collected and IL-1e production was assessed by ELISA. In parallel, control samples treated with vehicle alone were used in each experiment. The final concentration of DMSO was 1%. The compounds showed a dose-dependent increase in IL-1β production in PMA-differentiated THP-1 cells.

Measurement of ΙΙ-1β production in PMA-differentiated THP-1 cells (alternative method).

THP-1 cells were obtained from the American Type Culture Collection and subcultured according to the supplier's instructions. Prior to experiments, cells were cultured in RPMI 1640 medium containing 10% heat-inactivated FBS, penicillin (100 units/mL), streptomycin (100 μg/mL), HEPES (10 mM), and sodium pyruvate (1 mM), and maintained at log- phase before the start of the experiment. Prior to the experiment, THP-1 cells were treated with PMA (phorbol-12-myristate-13-acetate) (20 μg/ml) overnight. On the day of the experiment, the medium was removed and the attached cells were trypsinized for 2 min, then the cells were collected, washed with PBS (phosphate buffered saline), pelleted by centrifugation and resuspended in 2% heat inactivated FBS with RPMI at a concentration of 50,000 cells/well in 384- well plate. The cell-free supernatant was collected and ΙΙ-1β production was assessed by ELISA. The compounds were dissolved in dimethyl sulfoxide (DMSO) and added to the culture medium until the desired concentration was reached (eg 100, 30, 10, 3, 1, 0.3 or 0.1 μM). Cells were incubated with compounds for 2 hours. In parallel, control samples treated with vehicle alone were used in each experiment. The final concentration of DMSO was 1%. The compounds showed a dose-dependent increase in ΙΙ-1β production in PMA differentiated THP-1 cells.

Measurement of ΙΙ-1β production - hTRF protocol (second alternative method).

Serial dilutions of compounds in DMSO were added to low volume 384-well plates at 100 nl/well using an ECHO 550 acoustic dispenser (Labcyte) until a final starting concentration of 10 μM was reached in the assay.

THP-1 cells in RPMI medium (Gibco, 11875) with 10% FBS at a density of 1x10 ⁶ cells/ml in a T175 flask were treated with phorbol-12-myristate-13-acetate (PMA) (Sigma, P1585) at a final concentration of 50 ng/ml ml overnight at 37°C and 5% CO2 for differentiation. Cells were harvested the day after the well was washed with dPBS using 0.5% trypsin. A cell solution was prepared from 1x10 ⁶ cells/ml for 50,000 cells in 50 μl/well in RPMI medium with 2% FBS. Cells were plated using a multichannel pipette for compound dilutions in Greiner 384-well tissue cultured black clear bottom plates (781090). The plates were incubated in an incubator at 37°C at 5% CO2 for 2 h.

After incubation for 2 hours, the plates with cells were rotated in a centrifuge for 5 minutes at 1200 rpm. Using Felix (CyBio), 8 μl of the supernatant was transferred into 384-well, small volume, white proxy plates. (Perkin Elmer, 6008230). The Human ILbeta hTRF kit was used to analyze the supernatant (CISBIO, 62HIL1BPEG). Instructions were included with the kit to generate a standard ILlBeta curve, and then the antibodies from the kit were diluted 1:40 instead of 1:20 as indicated in the kit instructions. After pooling, the antibodies were added to the plates, 5 μl/well. The plates were sealed and incubated at 4°C overnight. The plates were then read on a Perkin Elmer EnVision at 665/615 nm using an hTRF laser. The compounds showed a dose-dependent increase in IL-1e production.

Measurement of IL-1e production - analysis of human whole blood.

Serial dilutions of compounds in DMSO were added to low volume 384-well plates at 100 μl/well using an ECHO 550 acoustic dispenser (Labcyte) until a final starting concentration of 10 μM was reached in the assay.

Human venous whole blood from healthy donors was pretreated with LPS (Invivogen, catalog number tlrl-eblps) at 1 ng/mL for four hours at 37° C. in a 95% humidified air, 5% CO2 incubator. The primed blood was added to the compound plate and incubated for an additional 4 hours at 37°C. IL-1beta in supernatants was measured using the AlphLISA kit (catalog number AL220) according to the manufacturer's instructions. The compounds showed a dose-dependent increase in IL-1e production. EC ₅₀ was determined using primed but untreated blood as baseline.

Measurement of IL-1e production - mouse hTRF protocol.

Immortalized mouse macrophages derived from C57BL/6 mice were obtained from Ericke

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Latz, University of Bonn/University of Massachusetts Worchester, MA. Cells were harvested using 0.05% trypsin and washed with PBS. Cells were seeded at a density of 30,000 cells per well in 25 μl of DMEM (Gibco, 11965) supplemented with 2% FBS and incubated for 10 min at 37°C and 5% CO ₂ . LPS-EB (Invivogen, tlr-eblps) was added to a final concentration of 200 ng/ml at 5 μl/well and the cells were incubated for 2 hours at 37°C and 5% CO2.

Serial dilutions of compounds in DMSO were added to cells in low volume 384-well plates at 60 μl/well using an ECHO 550 acoustic dispenser (Labcyte) to reach a final initial concentration of 50 μM in the assay and incubated with compounds for an additional 2 h at 37 °C at 5% CO ₂ .

After incubation for 2 hours, the plates with cells were rotated in a centrifuge for 5 minutes at 1200 rpm. Using Felix (CyBio), 8 μl of the supernatant was transferred into 384-well, small volume, white proxy plates. (Perkin Elmer, 6008230). The Human IL1beta hTRF kit was used to analyze the supernatant (CISBIO, 62MIL1BPEH). To construct the standard IL1Beta curve, the instructions that came with the kit were followed (antibodies from the kit were diluted 1:40, not 1:20 as indicated in the kit instructions). After pooling, the antibodies were added to the plates at 5 μl/well. The plates were sealed and incubated at 4°C overnight. The plates were then read on a Perkin Elmer EnVision at 665/615 nm using an hTRF laser. The data were then converted to pg/ml IllBeta. The compounds showed a dose-dependent increase in II.-1 β production.

In vitro human TLR7 and TLR8 binding reporter assays.

Logarithmically growing human HEK-Blue cells co-expressing the TLR7 or TLR8 gene and NF-kB/AP1-inducible reporter gene SEAP (Secreted Embryonic Alkaline Phosphatase; Invivogen, San Diego, CA) were added to individual wells of a 384-well plate (15,000 cells per 20 µl per well) and maintained for 24 h at 37°C, 5% CO2. Test compounds or DMSO were dispensed into individual wells the following day using sonic fluid technology (100 nL per well) and cells were then incubated for 18 hours at 37°C, 5% CO2. Cellular SEAP production was measured with an Envision plate reader thirty minutes after freshly prepared Quanti-Blue reagent (prepared according to manufacturer's instructions; Invivogen, San Diego, CA) was added to HEK-Blue TLR Nf-kB-SEAP cellular reactions. All EC ₅₀ values (half maximum effective concentration) were determined using proprietary data analysis software. Normalized EC5 ₀ value =absolute value determined by setting 100% Ymax using RLU (Relative Light Units) reference standard values for cells treated with 50 μM reference standard.

The table includes biological data for compounds that have been analyzed using one or more of the above methods. Key to activity ranges: A=<1 μM; B=>1 µM, <20 µM; С=>20 µM, <100 µM; D=>100 μM.

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Etc. No. NLRP3 hILIB EC ₅₀ (µM) TLR7 Agonist EC50 (µM) TLR8 Agonist EC50 (µM) 1 0.45 D D 2 0.43 WITH WITH 3 0.56 D D 4 16.8 D D 5 0.35 D D 6 0.56 D D 7 0.42 D D 8 0.89 D D 9 0.57 D D 10 1.00 WITH IN eleven 2.09 WITH D 12 1.52 WITH WITH 13 1.78 WITH D 14 1.68 WITH WITH 15 1.81 WITH D 16 11.3 WITH D 17 2.20 WITH D 18 1.13 WITH D 19 3.88 WITH WITH 20 1.08 WITH D 21 2.08 WITH D 22 0.63 WITH D 23 1.39 D D 24 2.90 D D 25 0.26 D D 26 0.98 D D 27 0.43 D D 28 1.31 D D 29 6.01 D D

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thirty 0.77 D D 31 0.15 WITH IN 32 14.7 IN D 33 11.8 D D 34 8.85 WITH D 35 20.7 WITH D 36 1.38 WITH D 37 0.95 D D 38 4.93 D D 39 0.25 D WITH 40 0.78 D D 41 0.80 D D 42 0.67 D D 43 0.46 D D 44 0.63 D D 45 1.41 D D 46 4.19 D D 47 23.3 D D 48 5.20 D D 49 0.61 D WITH 50 1.43 D D 51 18.8 D D 52 0.62 D D 53 0.45 D D 54 0.19 WITH D 55 0.39 WITH WITH 56 0.31 WITH IN 57 2.21 D D 58 0.30 D IN 59 0.47 D D 60 0.27 D D

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61 0.12 WITH D 62 0.28 With D 63 1.61 D D 64 0.48 D D 65 0.35 D WITH 66 0.80 D D 67 0.38 D D 68 0.37 D WITH 69 0.70 D D 70 1.83 D D 71 0.81 WITH WITH 72 0.14 WITH WITH 73 2.96 D D 74 0.25 D WITH 75 0.64 D D 76 0.33 D D 77 1.68 D D 78 4.71 D D 79 1.59 D D 80 2.07 D WITH 81 0.68 D WITH 82 0.73 D WITH 83 0.36 D D 84 1.79 D D 85 0.40 WITH WITH 86 2.77 D D 87 1.03 D D 88 0.13 WITH WITH 89 0.12 D IN 90 0.08 WITH WITH 91 1.17 D WITH

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92 1.07 D D 93 0.63 D D 94 0.21 D C 95 0.09 D D 96 0.31 D C 97 0.23 D D 98 1.59 D D 99 0.46 C D 100 1.67 D D 101 2.39 D D 102 0.41 C C 103 0.65 D D 104 0.13 C IN 105 0.98 C D 106 1.91 C C 107 2.63 D D 108 0.91 C C 109 1.78 C C BY 13.1 C IN 111 2.09 C D 112 2.50 D D 113 3.83 C D 114 4.84 D D 115 7.76 D D 116 7.43 D D 117 0.57 D C 118 0.86 D D 119 9.02 D D 120 1.87 D C 121 0.85 D D 122 5.99 D D

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123 9.02 D D 124 9.76 D D 125 8.34 D D 126 5.34 D D 127 1.05 D D 128 0.36 D D 129 0.70 D D 130 0.64 D D 131 0.61 D D 132 0.34 D C 133 0.30 D D 134 0.37 C D 135 0.98 D D 136 0.16 C D 137 1.67 D D 138 3.92 D D 139 7.80 D D 140 1.65 D D 141 6.28 D A 142 1.50 D C 143 0.40 D D 144 0.66 D D 145 2.74 D D 146 7.94 147 6.09 D D 148 2.03 149 0.38 D D 150 0.07 D D 151 0.06 D D 152 3.79 153 0.70 D D

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154 1.00 D D 155 0.01 D D 156 0.31 D D 157 5.17 D D 158 0.97 D C 159 0.68 D D 160 0.70 D D 161 5.82 D D 162 1.22 D D 163 0.06 D D 164 0.25 D D 165 0.14 D C 166 0.31 D D 167 0.15 D D 168 0.20 D C 169 0.39 D C 170 1.98 D D 171 0.60 D D 172 0.21 D D 173 0.21 D IN 174 0.23 IN C 175 0.29 D D 176 0.05 C C 177 2.23 D D 178 1.44 D D 179 25.83 D D 180 36.67 D D 181 6.53 D D 182 1.27 D D 183 0.11 D C 184 0.10 D

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185 0.21 IN D 186 0.21 IN D 187 0.22 D D 188 0.21 D D 189 0.59 D D 190 0.22 D D 191 7.19 D D 192 0.09 D D 193 0.24 WITH WITH 194 0.22 D D 195 2.15 D WITH 196 0.18 D D 197 0.25 D D 198 0.11 D D 199 4.44 D D 200 0.57 D D 201 0.48 D D 202 0.66 D D 203 3.49 D D 204 2.60 D D 205 2.04 D D 206 0.26 D D 207 0.14 D D 208 0.49 D D 209 0.19 D D 210 0.33 D D 211 0.63 D D 212 4.37 D D 213 3.21 D D 214 4.55 D D 215 0.40 D D

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216 3.04 D D 217 1.17 D D 218 0.20 D D 219 0.30 D D 220 0.12 D D 221 0.21 D D 222 0.27 D D 223 0.45 D D 224 0.14 D D 225 0.20 D D 226 0.44 D D 227 1.81 D D 228 0.30 D D 229 0.08 D D 230 0.87 D D 231 1.21 D D 232 1.87 D D 233 1.44 D D 234 0.56 D D 235 12.51 D D 236 0.79 D D 237 0.09 D D 238 0.72 D D 239 0.21 D D 240 0.62 D D 241 0.46 D D 242 0.68 D D 243 1.39 D D 244 1.80 D D 245 0.94 D D 246 0.58 D D

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247 0.44 D D 248 0.65 D D 249 0.64 D D 250 1.95 D D 251 0.62 D D 252 1.13 D D 253 0.30 D D 254 20.29 D D 255 10.92 D D 256 0.53 D D 257 0.86 D D 258 1.78 D D 259 2.29 D D 260 5.76 D D 261 1.29 D D 262 0.75 D D 263 1.66 D D 264 0.99 D D 265 2.47 D D 266 2.62 D D 267 1.07 D D 268 4.50 D D 269 4.38 D D 270 5.18 D D 271 1.07 D D 272 5.13 D D 273 5.16 D D 274 0.60 D D 275 1.73 D D 276 31.66 D D 277 2.33 D D

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278 0.75 D D 279 1.13 D D 280 1.72 D D 281 0.24 D D 282 0.10 D D 283 0.12 D D 284 0.25 D D 285 0.63 D D 286 0.41 D D 287 0.26 D D 288 0.45 D D 289 0.28 IN D 290 0.87 D D 291 4.65 D D 292 0.89 D D 293 0.60 D D 294 0.43 D D 295 0.42 D D 296 1.70 D D 297 2.83 D D 298 4.32 D D 299 2.92 D D 300 7.36 D D 301 1.40 D D 302 3.49 D D 303 0.21 D D 304 0.66 D D 305 0.29 D D 306 1.26 D D 307 0.43 D D 308 0.41 D D

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309 0.75 D D 310 0.75 D D 311 0.71 D D 312 0.22 D D 313 0.26 D D 314 0.49 D D 315 0.89 D D 316 0.89 D D 317 2.42 D D 318 3.09 D D 319 1.13 D D 320 6.57 D D 321 0.19 D D 322 0.83 D D 323 0.78 D D 324 1.57 D D 325 1.49 D D 326 0.22 D D 327 0.70 D D 328 1.35 D D 329 0.31 D D 330 0.17 D D 331 0.08 D D 332 0.21 D D 333 0.24 D D 334 0.11 D D 335 0.39 D D 336 0.47 D D 337 0.22 D D 338 0.39 D D 339 0.21 D D

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340 0.62 D D 341 0.43 D D 342 0.34 D D 343 0.61 D D 344 1.02 D D 345 2.03 D D 346 0.65 D D 347 0.30 D D 348 0.62 D D 349 0.35 D D 350 0.35 D D 351 0.64 D D 352 0.08 D D 353 0.61 D D 354 0.30 D D 355 2.57 D D 356 0.83 D D 357 0.19 D D 358 0.18 D D 359 1.45 D D 360 0.11 D D 361 0.19 D D 362 0.07 D D 363 1.84 D D 364 1.47 D D 365 1.88 D D 366 0.42 D D 367 0.23 D D 368 0.52 D D 369 0.19 D D 370 0.38 D D

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371 1.94 D D 372 0.88 D D 373 1.25 D D 374 0.65 D D 375 4.12 D D 376 0.40 D D 377 0.45 D D 378 0.64 D D 379 0.32 D D 380 0.77 D D 381 0.74 D D 382 5.39 D D 383 1.38 D D 384 0.88 D D 385 2.51 D D 386 0.21 D D 387 2.30 D D 388 0.31 D D 389 0.91 D D 390 0.35 D D 391 0.20 D D 392 0.08 D D 393 1.73 D D 394 0.46 D D 395 0.07 D D 396 0.65 D D 397 0.34 IN D 398 1.55 D D 399 0.23 D D 400 1.22 D D 401 2.66 D D

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402 0.31 D D 403 3.78 D D 404 0.74 D D 405 0.69 D D 406 0.45 D D 407 0.50 D D 408 1.94 D D 409 1.47 D D 410 0.33 D D 411 0.64 D D 412 1.87 D D 413 1.92 D D 414 2.80 D D 415 1.89 D D 416 0.15 D D 417 0.16 D D 418 3.65 D D 419 0.35 D D 420 0.51 D D 421 0.46 D D 422 0.14 D D 423 0.62 D D 424 3.21 D D 425 5.73 D D 426 1.89 D D 427 2.01 D D 428 1.81 D D 429 12.96 D D 430 1.90 D D 431 1.23 D D 432 3.19 D D

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433 4.58 D D 434 4.35 D D 435 3.61 D D 436 2.75 D D 437 0.56 D D 438 0.99 D D 439 0.32 D D 440 0.13 D D 441 1.33 D D 442 0.19 D D 443 0.23 D D 444 0.26 D D 445 0.66 D D 446 0.20 D D 447 0.38 D D 448 1.78 D D 449 0.70 D D 450 0.53 D D 451 1.26 D D 452 0.40 D D 453 0.31 D D 454 0.37 D D 455 0.22 D D 456 0.23 D D 457 0.16 D D 458 0.16 D D 459 0.27 D D 460 0.20 D D 461 0.25 D D 462 0.22 D D 463 0.13 D D

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464 0.24 D D 465 1.90 D D 466 0.61 D D 467 0.94 D D 468 1.62 D D 469 0.84 D D 470 15.35 D D 471 0.75 D D 472 0.23 D D 473 0.49 D D 474 0.45 D D 475 1.21 D D 476 0.51 D D 477 0.27 D D 478 0.35 D D 479 0.08 D D 480 0.26 D D 481 0.38 D D 482 2.21 D D 483 1.10 D D 484 1.41 D D 485 0.08 D D 486 0.13 D D 487 0.37 D D 488 1.15 D D 489 0.77 D D 490 0.84 D D 491 1.17 D D 492 0.76 D D 493 0.18 D D 494 1.89 D D

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495 0.45 D D 496 0.05 D D 497 0.05 D D 498 2.39 D D 499 1.34 D D 500 0.37 D D 501 0.73 D D 502 1.68 D D 503 2.58 D D 504 2.34 D D 505 29.6 D D 506 1.40 D D 507 17.5 D D 508 7.37 D D 509 6.95 D D 510 2.47 D D 511 4.62 D D 512 5.82 D D 513 1.28 D D 514 1.81 D D 515 4.09 D D 516 9.67 D D 517 1.72 D D 518 0.53 D D 519 2.07 D D 520 0.09 D D 521 5.67 D D 522 12.2 D D 523 7.30 D D 524 2.03 D D 525 20.2 D D

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526 0.70 D D 527 0.40 D D 528 0.51 D D 529 0.87 D D 530 0.68 D D 531 1.68 D D 532 0.34 D D 533 2.28 D D 534 0.71 D D 535 0.96 D D 536 3.58 D D 537 2.75 D D 538 0.60 D D 539 18.5 D D 540 3.13 D D 541 0.65 D D 542 1.58 D D 543 2.03 D D 544 4.36 D D 545 1.79 D D 546 3.27 D D 547 5.30 D D 548 0.78 D D 549 3.95 D D 550 5.01 D D 551 2.24 D D 552 9.89 D D 553 2.11 D D 554 0.46 D D 555 0.33 D D 556 1.82 D D

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557 0.42 D D 558 0.63 D D 559 0.60 D D 560 0.36 D D 561 0.95 D D 562 0.70 D D 563 9.21 D D 564 15.5 D D 565 4.18 D D 566 27.6 D D 567 0.97 D D 568 2.10 D D 569 0.94 D D 570 5.13 D D 571 2.02 D D 572 4.41 D D 573 6.59 D D 574 14.0 D D 575 19.7 D D 576 1.61 D D 577 2.32 D D 578 18.6 D D 579 4.47 D D 580 20.1 D D 581 3.17 D D 582 3.30 D D 583 1.82 D D 584 5.03 D D 585 3.88 D D 586 2.18 D D 587 2.39 D D

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588 10.9 D D 589 2.62 D D 590 1.20 D D 591 17.0 D D 592 0.68 D D 593 28.1 D D 594 7.94 D D 595 12.9 D D 596 10.1 D D 597 8.70 D D 598 1.98 D D 599 2.18 D D 600 3.99 D D 601 32.4 D D 602 21.2 D D 603 3.05 D D 604 0.85 D D 605 22.4 D D 606 2.46 D D 607 13.4 D D 608 0.70 D D 609 18.1 D D 610 4.41 D D 611 9.94 D D 612 0.43 D D 613 23.4 D D 614 11.6 D D 615 10.4 D D 616 9.56 D D 617 3.88 D D 618 14.5 D D 619 19.7 D D 620 28.6 D D 621 1.86 D D 622 7.28 D D 623 17.3 D D 624 19.9 D D

A number of embodiments of the invention have been described. However, it should be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (15)

CLAIM 1. Compound of formula (IIIb-1) R ⁴ (SHB-1) or its stereoisomer, tautomer or pharmaceutically acceptable salt, where R ² is independently selected from H, C ₁ _ ₄ alkyl substituted with 0-3 F, -(CH ₂ ) _1- 2CH(OH)CH ₂ F, -(CH ₂ )i- ₂ CH(OH)CF3, -( CH2)i-2CH(OH)CH2CF3, -(C^AOCHF^ -(CH2)i-3OCF3, -(CH2)i-2OCH2CF3, - (CH2)2-5OH, -(CH2)2-5CN, -(CH2)1-2CH(CH3)OH, -(CH2)1-2CH(CH3)CH2OH, -(CH2)1-2C(CH3) 2OH, -C(CH3)2(CH2)1-2OH, -(CH2)1-2C(CH3)2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C1-4alkyl), - CH (CH3) (CH2) 1-2OH, -CH ₂ CH (C1- ₂ alkyl) (CH ₂ ) 1- ₂ OH, -ODSSCHSmalkoxyXC^^OH, - (CH2) 2-4O (C1-4 alkyl substituted with 0-2 R ^e ), - (CH ₂ ) 1- ₂ CH (CH 3) O (C 1-4 α alkyl), - (CH ₂ ) 1- ₂ C (CH 3 ) ₂ O (C1.4αkyl), -CH (CH3) (CH2) 1-2O (C1-4 alkyl), -€H ₂ CH (OHCHCH ₂ ) 1- ₂ O (C1.4 alkyl), - (CH2) 1 -2CH(CH3)NH2, -CH ₂ C(CH3) ₂ NH ₂ , -(CH2)2-3NH(C1-4alkyl), -(ODC-3ZHSmalalkyl^, -( _CH2 )i-3C(O)NH ₂ , -(CH ₂ )i- ₂ C(CH3) ₂ CONH ₂ , - (cN ₂ ) ₁ . ₂ C(O)NH(C ₁ . ₄ alkyl substituted with 0-2 R ^e ), -(CH ₂ ) ₁ . ₂ C (O) N (CH ₃ ) (C _{1. 4} alkyl substituted with 0-2 R ^e ), - (CH 2) o-1CH (CH 3) (CH 2) o-1 C (O) NH (C 1.4 alkyl) , -(C ^ A ^ OMC malalkyl X, - (CH ₂ ) ₀ . ₁ CH (CH ₃ )C (O) N (C ₁ . ₄ alkyl) ₂ , -(CH ₂ ) ₁ . ₂ C (O) N (C ₁ . ₂ alkyl) (CH ₂ ) ₂ O (C ₁ . ₄ alkyl), - (CH ₂ ) ₂ . ₃ NHC(O)R ^a , -(CH2)1-2CH(CH3)NHC(O)R ^a , -CH2C(CH3)2NHC(O)R ^a , -(CH2)2-3N(CH3)C(O )R ^a , -(CH ₂ ) 2-3S(O) ₂ (C1.4alkylα), -CH2CH(CH3)S(O)2(C1.4alkyl), -(CH ₂ ) ₂ -3MH8(O) ₂ (C1.4alkyl), -CH ₂ CH (CH3) MH8 (O) ₂ (C _m alkyl), - (CH ₂ ) ₂ . ₃ NHS(О) ₂ (C ₃ . ₆ cycloalkyl), -(CH ₂ )1. ₃ -(heteroaryl containing from 5 to 10 ring atoms, with 1 to 4 ring atoms, each independently selected from N, N(R ^f ), O and S), and the specified heteroaryl is substituted with 0-2 R ^d ; R ³ is independently R ⁴ is independently H or F; R ^a is independently C1.4 alkyl substituted with 0-1 R ^e , C3. ₆ cycloalkyl substituted with 0-2 R ^d , phenyl or heteroaryl selected from oxazolyl, isoxazolyl, thiazolyl, pyridyl and pyrazinyl, wherein said phenyl and heteroaryl are substituted with 0-2 R ^d ; R ^d at each occurrence is independently selected from: F, Cl, OH, CN, Aralkyl, C ₁ . ₄ alkoxy, C ₁ . ₄ haloalkylα, NH ₂ , N(C _{1 .4} alkyl) ₂ , -NHC(O)(C _{1 .4} alkylα) and phenyl; R ^{e is} independently selected from: F, OH and C ₁ . ₄ alkoxy; And R ^f at each occurrence is independently selected from: H, C1. ₄ alkyl, -C (O) (C ₁ . ₄ alkyl) and -C (O) (C 1. ₄ haloalkyl). - 231 042018 2. Connection according to claim 1, where R ² is independently selected from H, C _1-4 alkyl substituted with 0-3 F, -(CH ₂ ) _1-2 CH(OH)CH ₂ F, -(CH2)i—2CH(OH)CF3, -(CH2 )i-2CH(OH)CH2CF3, -(CH2)i-2OCHF2, -(CCH3OCP3, -(C^LOC^CP3, - (CH ₂ ) _2-4 OH, -(CH ₂ ) _2-4 CN, -(CH ₂ ) _1-2 CH(CH ₃ )OH, -(CH ₂ ) _1-2 CH(CH ₃ )CH ₂ OH, -(CH ₂ ) _1-2 C(CH ₃ ) ₂ OH, -C(CH ₃ ) ₂ (CH ₂ ) _1-2 OH, -(CH ₂ ) _1-2 C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH (OH) CH ₂ OH, -CH ₂ CH (OH) (C _1-4 alkyl), - CH(CH3)(CH2)1-2OH, -CH2CH(C1-2alkyl)(CH2)1-2OH, -CH2CH(C1-4alkoxy)(CH2)1-2OH, -(SVD^O^^alkyl, substituted 0-1 R ^e ), -(CH ₂ ) _1-2 CH(CH ₃ )O(C _1-4 alkyl), -(CH ₂ ) _1-2 C(CH ₃ ) ₂ O(C _1-4 alkyl ), - CH(CH3)(CH2)1-2O(C1-4alkyl), -CH2CH(OH)(CH2)1-2O(C1-4alkyl), -(CH2)i-2CH(CH3)NH2, -CH2C(CH3 ^H2, -(CH2)2-3NH(C1-4alkyl), -(CH^CmalkylaD, -(CHX3CCO)^, -(CH2)i-2C(CH3)2CONH2, - (CH ₂ ) _1-2 C(O)NH(C _1-4 alkyl substituted with 0-2 R ^e ), -(CH2)1-2C(O)N(CH3)(C1-4 alkyl substituted with 0- 2 R ^e ), -(CH2) _0-1 CH(CH ₃ )(CH ₂ ) _0-1 C(O)NH(C _1-4 alkyl), -(CH ₂ ) _1-2 C(O)N (C _1-4 alkyl) ₂ , - (CH2)o-1CH(CH3)C(O)N(C1-4alkyl)2, -(CH2)1-2C(O)N(C1-2αkyl)(CH2)2O(C1-4αalkyl), -( CH2)2-3NHC(O)R ^a , -CH2CH(CH3)NHC(O)R ^a , -CH2C(CH ₃ ) ₂ NHC(O)R ^a , -(CH ₂ ) _2-3 S(O) ₂ (C _1-4 alkyl), -CH ₂ CH (CH ₃ ) S (O) ₂ (C _1-4 alkyl), - (CH 2) 2-3NHS (O) 2 (C 1-4 alkyl), -CH 2 CH (CH 3 )NHS(O)2(C1-4alkyl), -(CH2)2-3NHS(O)2(C3-6Cycloalkyl), and -(CH ₂ ) _1-2 (heteroaryl), wherein heteroaryl is selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, pyridyl and pyridazinyl, and heteroaryl is substituted with 0-2 R ^d ; R ^a is independently C _1-4 alkyl substituted with 0-1 R ^e , 1-2 phenyl or heteroaryl selected from oxazolyl, pyridyl and pyrazinyl, wherein said phenyl and heteroaryl are substituted with 0-2 R ^d ; And R ^d at each occurrence is independently selected from: F, Cl, CN, C _1-4 alkyl, C _1-4 alkoxy, and C 1 _-4 haloalkyl. 3. The compound according to any one of claims 1 or 2, which is a compound of formula (IIIb-2) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is independently selected from H, C _1-4 alkyl substituted with 0-3 F, -(CH ₂ ) _2-4 OH, -(CH ₂ ) _2-4 CN, -(CH2)1-2CH(CH3)OH, -(CH2)1-2C(CH3)2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)(C1-4alkyl), - 232 042018 - CH(CH3)(CH2)1-2OH, -CH2CH(C1-2alkyl)(CH2)1-2OH, -CH2CH(C1-2alkoxy)(CH2)1-2OH, - (CH ₂ ) _2-4 O (C _1-4 alkyl substituted with 0-2 R ^e ), -CH ₂ C (CH ₃ ) ₂ NH ₂ , -(CH ₂ ) _1-3 C (O) NH ₂ , -(CH ₂ ) _1-2 C(CH ₃ ) ₂ CONH ₂ , -(CH ₂ ) _1-2 C(O)NH(C _1-4 alkyl), -(CH ₂ ) _0-1 CH(CH ₃ ) (CH ₂ ) _0-1 C (O) NH (C _1-4 alkyl), - (CH ₂ ) _1-2 C (O) N (C _1-4 alkyl) ₂ , - (CH 2) o- 1CH(CH3)C(O)N(C1-4alkyl)2, -(CH2)1-2C(O)NH(C1-4alkyl substituted with 0-2R ^e ), - (CH ₂ ) _1-2 C(O)N(CH ₃ )(C _1-4 alkyl substituted with 0-2 R ^e ), -CH ₂ CH(CH ₃ )NHC(O)(C _1-4 alkyl ), - (CH2)2-3S(O)2(C1-4alkyl), -CH2CH(CH3)S(O)2(C1-4alkyl), -(CH2)2-3NHS(O)2(C1-4alkyl), - CH ₂ CH (CH ₃ )NHS (O) ₂ (C _1-4 alkyl), - (CH ₂ ) _2-3 NHS (O) ₂ (C _3-6 cycloalkyl), R ^{e is} independently selected from F, OH and C _1-4 alkoxy. 4. Connection according to claim 3, where R ² is independently selected from H, -CH2CHF2, -(CH^OH -(CH^CN, -CH2CH(CH3)OH, -CH2CH3^OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH2CH3, -CH( CH3)(CH2)2OH, -CH2CH(CH3)CH2OH, - CH ₂ CH (OCH _s ) CH ₂ OH, -(CH ₂ ) ₂ O (CH ₂ ) ₂ OH, -(CH ₂ ) ₂ O (CH ₂ ) ₂ OCH ₃ , -CH ₂ C (CH ₃ ) ₂ NH ₂ , -(CH ₂ ) _1-3 C(O)NH ₂ , -CH2C(CH3)2CONH2, -(CH2)1-2C(O)NH(CH3), -(CH2)1-2C(O) NH(CH2CH3), -(CH2)i-2C(O)NH(CH(CH3M -(CH ₂ ) _0-1 CH(CH ₃ )(CH ₂ ) _0-1 C(O)NH(CH ₃ ), -(CH ₂ ) _0-1 CH(CH ₃ )C(O)NH(CH(CH ₃ ) ₂ ), -(CH ₂ ) _1-2 C(O)N(CH ₃ ) ₂ , -(CH2) o-iCH(CH3)C(0)N(CH3)2, -CH2C(O)NH(CH2CHF2), -(CH2)1-2C(O)NH(CH2)2OH, - (CH ₂ ) _1-2 C(O)NH(C(CH ₃ ) ₂ CH ₂ OH), -(CH ₂ ) _1-2 C(O)NH(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) _1-2 C(O)N(CH ₃ )(CH ₂ ) ₂ OCH ₃ , -CH2CH(CH3)NHC(O)(CH3), -(CH2)2-3S(O)2CH3, -(CH^OW^, -(CH2)2-3NHS(O)2CH3, - CH ₂ CH(CH ₃ )NHS(O) ₂ CH ₃ , -(CH ₂ ) _2-3 NHS(O) ₂ (cyclopropyl), 5. Connection selected from: - 233 042018 - 234 042018 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof. 6. Compound Formula or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof. 7. Compound Formula or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof. 8. Compound Formula or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof. 9. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and one or more pharmaceutically acceptable excipients. - 235 042018 10. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of pi. 1-8, or a pharmaceutical composition according to and. 9 for the manufacture of a drug for the treatment of cancer. 11. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of pi. 1-8, or a pharmaceutical composition according to and. 9 for cancer treatment. 12. Application according to and. 11, where the cancer is selected from acute myeloid leukemia, adrenocortical carcinoma, Kaposi's sarcoma, lymphoma, anal cancer, appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer gland, bronchial tumor, carcinoid tumor, heart tumor, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile duct cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma , eye cancer, fallopian tube cancer, gallbladder 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 myelogenous leukemia, lip and oral cancer, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, oropharyngeal cancer, oral cancer, osteosarcoma, ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer, rectal cancer, salivary gland cancer , skin cancer, small bowel cancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, and vulvar cancer. 13. Application according to and. 12, where the cancer is selected from breast cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, and prostate cancer. 14. Application according to and. 13, wherein the cancer is selected from hormone receptor positive breast cancer, microsatellite stable colon or rectal cancer, pancreatic cancer, and prostate cancer. 15. Application according to any of pi. 11-14 wherein the compound is administered in combination with one or more adjunctive cancer therapies.