TW201936614A - Compounds and compositions as inhibitors of endosomal TOLL-LIKE receptors - Google Patents

Compounds and compositions as inhibitors of endosomal TOLL-LIKE receptors Download PDF

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TW201936614A
TW201936614A TW107106302A TW107106302A TW201936614A TW 201936614 A TW201936614 A TW 201936614A TW 107106302 A TW107106302 A TW 107106302A TW 107106302 A TW107106302 A TW 107106302A TW 201936614 A TW201936614 A TW 201936614A
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methyl
pyrazolo
pyridin
oct
tetrahydro
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TW107106302A
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Chinese (zh)
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TWI772370B (en
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飛利普 艾伯
強納森 狄恩
松春 蔣
濤 江
湯瑪士 諾費爾
皮爾-耶維斯 米其林
丹尼爾 穆特尼
裴偉
彼得 夕卡
國寶 張
張易
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瑞士商諾華公司
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Abstract

The invention disclosed herein relates to 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridinyl compounds and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinyl compounds of Formula (A), pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment of autoimmune diseases.

Description

作為胞內體類鐸（TOLL-LIKE）受體抑制劑之化合物及組合物Compounds and compositions as endosome steroid (TOLL-LIKE) receptor inhibitors

本發明提供4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶化合物及4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶化合物，其用於抑制胞內體類鐸(Toll-like)受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之用途，其用於抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合之用途，及使用此等化合物治療自體免疫疾病之方法。The present invention provides a 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine compound and 4,5,6,7-tetrahydro-2H-pyrazolo[4,3- c] a pyridine compound for inhibiting endogenous toll-like receptors (eg, TLR7, TLR8 or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8/9) , the use of TLR7/9 and TLR8/9) for inhibiting the use of endogenous receptors (eg, TLR7, TLR8 or TLR9) and any combination thereof, and the use of such compounds for the treatment of autoimmune diseases The method.

病原體之特定類別之早期偵測係藉由先天免疫系統在模式識別受體(PRR)之幫助下完成。類鐸受體(TLR)係模式識別受體，其等藉由識別微生物病原體之入侵及開始細胞內信號轉導通路以引發基因(其等產物可控制先天免疫反應)之表現而在先天免疫力中發揮重要作用。人類基因體中有10種TLR，其中TLR1、TLR2、TLR4、TLR5及TLR6回應於細胞外刺激，而TLR3、TLR7、TLR8及TLR9回應於細胞漿內病原體相關分子模式(PAMP)，其與內溶酶體腔室相關聯。 類鐸受體識別存在於由病原體廣泛分享但結構上不同於宿主分子之分子中之病原體相關分子模式。此等受體之配體係高度保守之微生物分子，諸如脂多醣(LPS) (由TLR4識別)、脂肽(TLR2與TLR1或TLR6組合)、鞭毛蛋白(TLR5)、單股RNA (TLR7及TLR8)、雙股RNA (TLR3)、含有CpG基序之DNA (由TLR9識別)及存在於尿道致病菌上之抑制蛋白(TLR 11)。因此，包括TLR4-MD-2、TLR1-TLR2及TLR6-TLR2之細胞表面TLR二聚物識別微生物膜脂質，而胞內體類鐸受體TLR3、TLR7、TLR8及TLR9存在於細胞內細胞器中並識別微生物核酸。 TLR7、TLR8及TLR9基於其等基因體結構、序列相似性及同源性而屬於TLR之子家族。TLR7、TLR8及TLR9係位於細胞內內溶酶體腔室中並顯示認為負責不同病原體反應特性之細胞類型特異性表現之獨特模式。 除識別外來材料外，TLR亦可錯誤地回應於自身產物並引起自體免疫疾病。TLR7及9 (分別係用於微生物RNA或DNA之先天免疫感測器)已涉及自體免疫疾病，諸如牛皮癬(參見Lande等人，「Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide」，Nature 449，第564至569頁，2007)、關節炎(參見Asagiri等人，「Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis」，Science 319，第624至627頁，2008)及全身性紅斑狼瘡(SLE) (參見Pisitkun, P.等人，「Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication」，Science 312，第1669至72頁，2006；Deane, J.A.等人，「Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation」，Immunity，27，第801至10頁，2007；Christensen, S.R.等人，「Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus」，Immunity 25，第417至428頁，2006；Ehlers, M.等人，「TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE」，J. Exp. Med. 203，第553至561頁，2006；Deane, J.A.及Bolland S. 「Nucleic acid-sensing TLRs as modifiers of autoimmunity」，J. I mmunol., 117，第6573至8頁，2006；及Marshak-Rothstein, A.及Rifkin, I.R.，「Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease」，Annu. Rev. I mmunol., 25，第419至441頁，2007)。 已顯示自體免疫係由自身核酸對內溶酶體之異常運輸加劇(參見Lande等人，2007；Marshak-Rothstein及Rifkin, 2007；及Leadbetter等人，「Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors」，Nature，416，第603至607頁，2002)。在諸如SLE之自體免疫疾病中，自身RNA及自身DNA係與針對核酸或核蛋白質之自身抗體複合，經由FcgRII介導之內吞作用遞送至胞內體腔室內，導致樹突細胞(DC)活化及I型干擾素(IFN)之產生(Barrat等人，「Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus」，J. Exp. Med. 202，第1131至1139頁，2005)。而在牛皮癬中，自身DNA及自身RNA與陽離子抗微生物肽LL37形成複合物，接近DC之內溶酶體之TLR7及9，並誘導IFN-a之異常產生(Ganguly等人，「Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8」，J. Exp. Med. 206，第1983至1994頁，2009；及Lande等人，2007)。在類風濕性關節炎(RA)中，滑膜係由經活化之免疫細胞(主要是巨噬細胞及T細胞)浸潤，從而導致促炎細胞介素及基質金屬蛋白酶之慢性產生。TNF在RA中發揮主要作用及TLR8之抑制已顯示抑制TNF產生(參見Sandra M. Sacre等人，「Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures」，J. Immun., 81，第8002至8009頁，2008)。 因為TLR7、TLR8及TLR9與自體免疫疾病相關聯，所以已表明TLR7、TLR8及TLR9係用於全身性紅斑狼瘡、類風濕性關節炎、牛皮癬及其他自體免疫疾病之治療之重要治療目標。Early detection of a particular class of pathogens is accomplished with the help of a pattern recognition receptor (PRR) by the innate immune system. Terpenoid receptors (TLRs) are pattern recognition receptors that recognize innate immunity by recognizing the invasion of microbial pathogens and initiating intracellular signal transduction pathways to trigger the expression of genes that control their innate immune responses. Play an important role. There are 10 TLRs in human genomes, of which TLR1, TLR2, TLR4, TLR5 and TLR6 respond to extracellular stimulation, while TLR3, TLR7, TLR8 and TLR9 respond to intracellular pathogen-associated molecular patterns (PAMP), which are compatible with endoplasmic The enzyme body chamber is associated. The guanidine receptor recognition exists in a pathogen-associated molecular pattern that is widely shared by the pathogen but is structurally different from the host molecule. Microbial molecules with highly conserved systems of such receptors, such as lipopolysaccharide (LPS) (identified by TLR4), lipopeptides (in combination with TLR2 and TLR1 or TLR6), flagellin (TLR5), single-stranded RNA (TLR7 and TLR8) , double-stranded RNA (TLR3), DNA containing CpG motif (identified by TLR9), and inhibitory protein (TLR 11) present on urethra pathogens. Thus, cell surface TLR dimers including TLR4-MD-2, TLR1-TLR2, and TLR6-TLR2 recognize microbial membrane lipids, while intracellular steroid receptors TLR3, TLR7, TLR8, and TLR9 are present in intracellular organelles. And identify microbial nucleic acids. TLR7, TLR8 and TLR9 belong to a subfamily of TLRs based on their isogenic structure, sequence similarity and homology. TLR7, TLR8 and TLR9 are located in the intracellular lysosomal compartment and display a unique pattern of cell type-specific expression that is believed to be responsible for the response characteristics of different pathogens. In addition to identifying foreign materials, TLRs can also erroneously respond to their own products and cause autoimmune diseases. TLRs 7 and 9 (innate immune sensors for microbial RNA or DNA, respectively) have been involved in autoimmune diseases such as psoriasis (see Lande et al., "Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide", Nature 449 , pp. 564-569, 2007), arthritis (see Asagiri et al., "Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis", Science 319, pp. 624-627, 2008) and systemic erythema Lupus (SLE) (see Pisitkun, P. et al., "Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication", Science 312, pp. 1669-72, 2006; Deane, JA et al., "Control of Toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation", Immunity, 27, pp. 801-10, 2007; Christensen, SR et al., "Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have in inflammatory And regulatory roles in a murine model of lupus", Immunity 25, pp. 417-428 , 2006; Ehlers, M. et al., "TLR9/MyD88 signaling is required for class switching to pathogenic IgG2a and 2b autoantibodies in SLE", J. Exp. Med. 203, pp. 553-561, 2006; Deane, JA and Bolland S. "Nucleic acid-sensing TLRs as modifiers of autoimmunity", J. I mmunol., 117, pp. 6573-8, 2006; and Marshak-Rothstein, A. and Rifkin, IR, "Immunologically active autoantigens: the role Of toll-like receptors in the development of chronic inflammatory disease", Annu. Rev. I mmunol., 25, pp. 419-441, 2007). The autoimmune line has been shown to be exacerbated by the abnormal transport of endolysosomes by self-nucleic acids (see Lande et al., 2007; Marshak-Rothstein and Rifkin, 2007; and Leadbetter et al., "Chromatin-IgG complexes activate B cells by dual engagement Of IgM and Toll-like receptors", Nature, 416, pp. 603-607, 2002). In autoimmune diseases such as SLE, autologous RNA and self-DNA lines are complexed with autoantibodies against nucleic acids or nuclear proteins, delivered to the intracellular body via FcgRII-mediated endocytosis, resulting in dendritic cell (DC) activation. And the production of type I interferon (IFN) (Barrat et al, "Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus", J. Exp. Med. 202, 1131 to 1139 pages, 2005). In psoriasis, self DNA and autoRNA form a complex with the cationic antimicrobial peptide LL37, which is close to the lysosome TLR7 and 9 in DC, and induces abnormal production of IFN-a (Ganguly et al., "Self-RNA- Antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8", J. Exp. Med. 206, pp. 1983-1994, 2009; and Lande et al., 2007). In rheumatoid arthritis (RA), the synovial system is infiltrated by activated immune cells (primarily macrophages and T cells), resulting in the chronic production of pro-inflammatory interleukins and matrix metalloproteinases. TNF plays a major role in RA and inhibition of TLR8 has been shown to inhibit TNF production (see Sandra M. Sacre et al., "Inhibitors of TLR8 Reduce TNF Production from Human Rheumatoid Synovial Membrane Cultures", J. Immun., 81, pp. 8002 8009 pages, 2008). Because TLR7, TLR8, and TLR9 are associated with autoimmune diseases, TLR7, TLR8, and TLR9 have been shown to be important therapeutic targets for the treatment of systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and other autoimmune diseases.

仍存在針對自體免疫疾病(特定言之與TLR7、TLR8及/或TLR9活性相關聯之自體免疫疾病)之新穎治療及療法之需求。本發明提供可抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之化合物、其醫藥上可接受之鹽、其醫藥組合物。另外，本發明之化合物可抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合。本發明進一步提供治療、預防或減輕與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病之方法，該方法包括向有此需要之個體投與有效量之本發明之化合物。本文描述本發明之各種實施例。 在本發明之一項態樣中係具有式(A)結構之化合物及其醫藥上可接受之鹽，其等可抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)。另外，式(A)化合物可抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合：式(A) 其中， RA 係、、、、、、、、、或； L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -、-XCH2 -或-CH2 X-； X係-CH2 -或O； R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、 -NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、 -NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 、-NHC(=O)(CH2 )n NR9 S(=O)2 R5 、、、8-氧雜-3-氮雜雙環[3.2.1]辛基、具有獨立地選自N、O及S之1至3個環成員之5至6員雜芳基及具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 個基團取代； R2 係H、C1 -C6 烷基、C1 -C6 鹵烷基或經1至2個R15 基團取代之C1 -C6 烷基； R3 係H、C1 -C6 烷基、-CD3 或經1至2個R10 基團取代之苄基； R4 係H、NH2 、C1 -C6 烷基、鹵基或經0至2個R18 基團取代之苯基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基、氧雜-3-氮雜雙環[3.2.1]辛烷或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R7 係獨立地選自C1 -C6 烷基、鹵基、羥基、側氧基及經1至3個-OH取代之C1 -C6 烷基； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R10 係C1 -C6 烷氧基或C3 -C6 環烷基； R11 係未經取代或經1至3個C1 -C6 烷基取代之C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； R15 係-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CHR9 )n R6 、-N(R6 )2 、-N(CD3 )2 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 ； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 在此等式(A)化合物之某些實施例中係式(I)及式(II)化合物： 式(I) 式(II)。 本發明之另一態樣係包括治療有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑之醫藥組合物。 本發明之另一態樣係式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽在製造用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病之藥劑中之用途。 本發明之另一態樣係式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽在製造用於治療與以下相關聯之自體免疫疾病之藥劑中之用途： i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性。 本發明之另一態樣係式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽在製造用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合之活性相關聯之自體免疫疾病之藥劑中之用途。 本發明之另一態樣係式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽在製造用於治療自體免疫疾病之藥劑中之用途。 本發明之另一態樣係式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽在製造用於治療自體免疫疾病之藥劑中之用途，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群(Sjögren’s syndrome)、關節炎、類風濕性關節炎或牛皮癬。在此態樣之一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、休格倫症候群或牛皮癬。 本發明之另一態樣係用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 本發明之另一態樣係用於治療與以下相關聯之自體免疫疾病之方法： i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性， 其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 本發明之另一態樣係用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合之活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 本發明之另一態樣係用於治療與TLR7活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 本發明之另一態樣係用於治療與TLR7及TLR8活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 本發明之另一態樣係用於治療與TLR7、TLR8及TLR9活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，藉此治療該疾病。 在治療之此等方法之某些實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、休格倫症候群或牛皮癬。 本發明之另一態樣係用於治療自體免疫疾病之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。在此態樣之一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、休格倫症候群或牛皮癬。 本發明之另一態樣係包含治療有效量之式(A)、式(I)或式(II)或其子式化合物或其醫藥上可接受之鹽及一或多種額外之治療劑且視需要進一步包含醫藥上可接受之載劑之組合，其中該額外之治療劑係獨立地選自抗炎劑、免疫調節劑、免疫抑制劑、細胞介素、非類固醇抗炎藥物(NSAID)、抗瘧化合物、抗風濕化合物、B細胞活化因子(BAFF)之抑制劑、B淋巴細胞刺激劑(BLyS)之抑制劑及類固醇激素。There remains a need for novel therapies and therapies for autoimmune diseases, in particular autoimmune diseases associated with TLR7, TLR8 and/or TLR9 activity. The invention provides for inhibition of endosome receptors (eg, TLR7, TLR8 or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) a compound, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof. In addition, the compounds of the invention may inhibit endogenous steroid receptor (eg, TLR7, TLR8 or TLR9) pathways, and any combination thereof. The invention further provides for the treatment, prevention or amelioration of endogenous steroid receptors (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9) And a method of autoimmune disease associated with the activity of TLR8/9), which comprises administering to a subject in need thereof an effective amount of a compound of the invention. Various embodiments of the invention are described herein. In one aspect of the invention is a compound having the structure of formula (A) and a pharmaceutically acceptable salt thereof, which inhibits endogenous receptors (eg, TLR7, TLR8 or TLR9) and any Combinations (including but not limited to TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9). In addition, the compounds of formula (A) inhibit the endogenous steroid receptor (eg, TLR7, TLR8 or TLR9) pathways and any combination thereof: Formula (A) where R A is , , , , , , , , , or ; L system -CH 2 - or -CH 2 CH 2 -; Y 1 system -CH 2 - or -CH 2 CH 2 -; Y 2 system -CH 2 - or -CH 2 CH 2 -; Y 3 system -CH 2 -, -XCH 2 - or -CH 2 X-; X--CH 2 - or O; R 1 -NHC(=O)R 6 , -NHC(=O)(CH 2 ) n R 6 ,- NH(CH 2 ) n C(=O)R 6 , -NHC(=O)(CH 2 ) m NHR 5 , -NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(= O)(CHR 9 ) m NHR 5 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CH 2 ) n OR 9 , -NHC(=O)OR 9 , -NH( CH 2 ) m C(=O)N(R 5 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , NHC(=O)(CHR 9 ) n R 6 , -NHC(=O) (CHR 9 ) n N(R 8 ) 2 , -NHC(=O)(CHR 9 ) n NHR 8 , -NH(CHR 9 ) n C(=O)N(R 8 ) 2 , -NH(CHR 9 m C(=O)R 6 , -NHR 6 , -NR 5 R 6 , -NH 2 , -N(R 5 ) 2 , -NHR 5 , -NHR 8 , -N(R 6 R 8 ), - NH(C(R 9 ) 2 ) n R 10 , -NR 9 C(=O)OR 11 , -NH(CH 2 ) n R 6 , -NH(CHR 9 ) n R 6 , -N(R 6 ) 2 , -NHC(=O)(CH 2 ) n N(CD 3 ) 2 , -NH(CHR 9 ) n CH 2 OR 9 , -NHCH 2 (CHR 9 ) n OR 9 , -NH(CHR 9 ) n OR 9 , -NR 9 (CH 2 ) n OR 9 , -NHCH 2 (C(R 9 ) 2 ) n OR 9 , -OR 9 , -NR 9 C(=O)R 5 , -NR 9 C(= O) (CH 2) n R 5, -NR 9 C (= O) OR 5 -NHS (= O) 2 R 5 , -NHC (= O) (CH 2) n NR 9 C (= O) R 5, -NHC (= O) (CH 2) n NR 9 S (= O) 2 R 5 , , , 8-oxa-3-azabicyclo[3.2.1]octyl, 5 to 6 membered heteroaryl having 1 to 3 ring members independently selected from N, O and S and independently selected from 4 to 6 membered heterocycloalkyl of 1 to 2 ring members of N, NH, NR 16 and O, which are unsubstituted or substituted with 1 to 2 R 7 groups; R 2 H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyl substituted with 1 to 2 R 15 groups; R 3 H, C 1 -C 6 alkyl, -CD 3 Or a benzyl group substituted with 1 to 2 R 10 groups; R 4 is H, NH 2 , C 1 -C 6 alkyl, halo or phenyl substituted with 0 to 2 R 18 groups; 5 is independently selected from C 1 -C 6 alkyl, -CD 3 and -(CH 2 ) n OR 9 ; R 6 is C 3 -C 6 cycloalkyl, oxa-3-azabicyclo[3.2. 1] octane or a 4 to 6 membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH, NR 16 and O, which are unsubstituted or have 1 to 2 R 12 groups Substituting; each R 7 is independently selected from C 1 -C 6 alkyl, halo, hydroxy, pendant oxy and C 1 -C 6 alkyl substituted with 1 to 3 -OH; each R 8 is independently Selected from C 1 -C 6 haloalkyl, -(C(R 9 ) 2 ) n OR 9 and C 1 -C 6 alkyl substituted by 1 to 3 -OH; R 9 is independently selected from H and C 1 -C 6 alkyl; R 10 is C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl; R 11 is unsubstituted or 1 to 3 C 1 -C 6 alkyl substituted C 3 -C 6 cycloalkyl; each R 12 is independently selected from C 1 -C 6 alkyl, hydroxy, halo and C 1 substituted by 1 to 3 -OH -C 6 alkyl; R 13 H or C 1 -C 6 alkyl; R 14 H or C 1 -C 6 alkyl; R 15 -NHC(=O)(CH 2 ) m NHR 5 , NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CHR 9 ) n R 6 , -NHC(=O )(CHR 9 ) n N(R 8 ) 2 , -NHC(=O)(CHR 9 ) n NHR 8 , -NH(CHR 9 ) n C(=O)N(R 8 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , -NHR 6 , -NH 2 , -N(R 5 ) 2 , -NHR 8 , -N(R 6 R 8 ), -NH(C(R 9 ) 2 ) n R 10 , -NR 9 C(=O)OR 11 , -NH(CHR 9 ) n R 6 , -N(R 6 ) 2 , -N(CD 3 ) 2 , -NH(CHR 9 ) n OR 9 Or -NHCH 2 (C(R 9 ) 2 ) n OR 9 ; each R 16 is C 1 -C 6 alkyl; each R 17 is independently selected from H and C 1 -C 6 alkyl; each R 18 system Independently selected from halo, -CN, C 1 -C 6 alkoxy and C 1 -C 6 alkyl; m series 1, 2, 3, 4, 5 or 6, and n series 1, 2, 3, 4, 5 or 6. In certain embodiments of the compounds of formula (A), the compounds of formula (I) and formula (II): Formula (I) Formula (II). Another aspect of the invention includes a therapeutically effective amount of a medicament of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier combination. Another aspect of the invention is a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a therapeutic and intracellular steroid receptor (eg, Use of an agent for autoimmune diseases associated with the activity of TLR7, TLR8 or TLR9) or any combination thereof, including but not limited to, TLR7/8, TLR7/8/9, TLR7/9 and TLR8/9 . Another aspect of the invention is a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of an autoimmune disease associated with the treatment of Uses in the medicament: i) TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity. Another aspect of the invention is a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a therapeutic and intracellular steroid receptor (eg, Use of an agent for autoimmune diseases associated with the activity of the TLR7, TLR8 or TLR9) pathways and any combination thereof. Another aspect of the invention is the use of a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease. Another aspect of the invention is the use of a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an autoimmune disease, The autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, multiple muscles Inflammation, Sjögren's syndrome, arthritis, rheumatoid arthritis or psoriasis. In one embodiment of this aspect, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, Hugh's syndrome or psoriasis. Another aspect of the invention is for use in the treatment of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7) A method of autoimmune disease associated with the activity of /9 and TLR8/9), wherein the method comprises administering to the individual in need of such treatment an effective amount of formula (A), formula (I) or formula (II) or A compound of the formula or a pharmaceutically acceptable salt thereof, whereby the disease is treated. Another aspect of the invention is a method for treating an autoimmune disease associated with: i) TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity, wherein The method comprises administering to an individual in need of such treatment an effective amount of a compound of formula (A), formula (I) or formula (II) or a sub-form thereof or a pharmaceutically acceptable salt thereof, thereby treating the condition. Another aspect of the invention is a method of treating an autoimmune disease associated with the activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, and any combination thereof, wherein the method comprises An individual in need of such treatment is administered an effective amount of a compound of formula (A), formula (I) or formula (II) or a sub-form thereof or a pharmaceutically acceptable salt thereof, whereby the condition is treated. Another aspect of the invention is a method of treating an autoimmune disease associated with TLR7 activity, wherein the method comprises administering to an individual in need of such treatment an effective amount of formula (A), formula (I) or A compound of the formula (II) or a sub-form thereof or a pharmaceutically acceptable salt thereof, whereby the disease is treated. Another aspect of the invention is a method of treating an autoimmune disease associated with TLR7 and TLR8 activity, wherein the method comprises administering to the individual in need of such treatment an effective amount of formula (A), formula (I) Or a compound of the formula (II) or a sub-form thereof or a pharmaceutically acceptable salt thereof, whereby the disease is treated. Another aspect of the invention is a method for treating an autoimmune disease associated with TLR7, TLR8 and TLR9 activity, wherein the method comprises administering to the individual in need of such treatment an effective amount of formula (A), (I) or a compound of the formula (II) or a sub-form thereof or a pharmaceutically acceptable salt thereof, whereby the disease is treated. In certain embodiments of such methods of treatment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenia Purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, Hugh's syndrome or psoriasis. Another aspect of the present invention is for the treatment of an autoimmune disease of the formula (A), the formula (I) or the formula (II) or a compound thereof or a pharmaceutically acceptable salt thereof, the autoimmune disease system Systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome , arthritis, rheumatoid arthritis or psoriasis. In one embodiment of this aspect, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, Hugh's syndrome or psoriasis. Another aspect of the invention comprises a therapeutically effective amount of a compound of formula (A), formula (I) or formula (II) or a subformulaic compound thereof, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, and It is further desired to further comprise a combination of pharmaceutically acceptable carriers, wherein the additional therapeutic agent is independently selected from the group consisting of an anti-inflammatory agent, an immunomodulator, an immunosuppressive agent, an interleukin, a non-steroidal anti-inflammatory drug (NSAID), an anti-inflammatory agent. Malaria compounds, anti-rheumatic compounds, inhibitors of B cell activating factor (BAFF), inhibitors of B lymphocyte stimulator (BLyS), and steroid hormones.

本文描述本發明之各種枚舉型實施例。將認知各實施例中規定之特徵可與其他規定特徵組合以提供本發明之其他實施例。定義 如本文使用之術語「C1 -C6 烷基」係指含有1至6個碳原子之完全飽和分支鏈或直鏈烴。「C1 -C6 烷基」之非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、異戊基及己基。 如本文使用之術語「C1 -C6 烷氧基」係指基團-O-C1 -C6 烷基，其中「C1 -C6 烷基」係如本文定義。「C1 -C6 烷氧基」之非限制性實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基、第三丁氧基、正戊氧基、異戊氧基及己氧基。 如本文使用之術語「環烷基」係指飽和、單環、稠合雙環、稠合三環或橋接多環形環系統。稠合雙環或橋接多環形環系統之非限制性實例包括雙環[1.1.1]戊烷、雙環[2.1.1]己烷、雙環[2.2.1]庚烷、雙環[3.1.1]庚烷、雙環[3.2.1]辛烷、雙環[2.2.2]辛烷及金剛烷基。如本文使用，術語「C3 -C6 環烷基」係指具有至少3個且最多6個碳原子之飽和單環基團。此等「C3 -C6 環烷基」之非限制性實例包括環丙基、環丁基、環戊基及環己基。 如本文使用之術語「C1 -C6 鹵烷基」係指個別如本文定義之「C1 -C6 烷基」，其中該「C1 -C6 烷基」之氫原子中之至少一者係經鹵原子置換。該等C1 -C6 鹵烷基可係單C1 -C6 鹵烷基，其中此等C1 -C6 鹵烷基具有一個碘、一個溴、一個氯或一個氟。另外，該等C1 -C6 鹵烷基可係二C1 -C6 鹵烷基，其中此等C1 -C6 鹵烷基可具有兩個獨立地選自碘、溴、氯或氟之鹵原子。此外，該等C1 -C6 鹵烷基可係聚C1 -C6 鹵烷基，其中此等C1 -C6 鹵烷基可具有兩個或多個相同之鹵原子或兩個或多個不同鹵原子之組合。此等聚C1 -C6 鹵烷基可係全鹵C1 -C6 鹵烷基，其中個別C1 -C6 烷基之所有氫原子已經鹵原子置換且該等鹵原子可相同或係不同鹵原子之組合。C1 -C6 鹵烷基之非限制性實例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、三氟乙基、二氟丙基、二氯乙基及二氯丙基。 如本文使用之術語「鹵基」或「鹵素」係指氟、氯、溴及碘。 如本文使用之術語「5至6員雜芳基」係指具有5或6個環成員之單環芳族環結構，其中1至3個環成員係獨立地選自雜原子N、O及S。5至6員雜芳基之非限制性實例包括2-或3-呋喃基；2-或3-噻吩基；1-、2-或3-吡咯基；2-、4-或5-噁唑基；2-、4-或5-噻唑基；1-、2-、4-或5-咪唑基；1-、3-、4-或5-吡唑基；3-、4-或5-異噁唑基；3-、4-或5-異噻唑基；4-或5-1,2,3-噁二唑基；4-或5-1,2,3-***基；2-或5-1,3,4-噻二唑基；2-、3-或4-吡啶基；3-、4-、5-或6-噠嗪基；2-、4-、5-或6-嘧啶基及2-或3-吡嗪基。 如本文使用之術語「雜原子」係指氮(N)、氧(O)或硫(S)原子。 如本文使用之術語「4至6員雜環烷基」係指具有4至6個環成員之單環形環結構，其中該等環成員之一至兩者係獨立地選自N、NH、NR16 、O或-S-，其中R16 係C1 -C6 烷基。在較佳實施例中，4至6員雜環烷基係具有4至6個環成員之單環形環結構，其中該等環成員之一至兩者係獨立地選自N、NH、NR16 及O，其中R16 係C1 -C6 烷基。如本文使用，4至6員雜環烷基之非限制性實例包括氮雜環丁烷基、氮雜環丁烷-1-基、氮雜環丁烷-2-基、氮雜環丁烷-3-基、氧雜環丁烷基、氧雜環丁烷-2-基、氧雜環丁烷-3-基、氧雜環丁烷-4-基、硫雜環丁烷基、硫雜環丁烷-2-基、硫雜環丁烷-3-基、硫雜環丁烷-4-基、吡咯啶基、吡咯啶-1-基、吡咯啶-2-基、吡咯啶-3-基、吡咯啶-4-基、吡咯啶-5-基、四氫呋喃基、四氫呋喃-2-基、四氫呋喃-3-基、四氫呋喃-4-基、四氫呋喃-5-基、四氫噻吩基、四氫噻吩-2-基、四氫噻吩-3-基、四氫噻吩-4-基、四氫噻吩-5-基、哌啶基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、哌啶-5-基、哌啶-6-基、四氫哌喃基、四氫哌喃-2-基、四氫哌喃-3-基、四氫哌喃-4-基、四氫哌喃-5-基、四氫哌喃-6-基、四氫噻喃基、四氫噻喃-2-基、四氫噻喃-3-基、四氫噻喃-4-基、四氫噻喃-5-基、四氫噻喃-6-基、哌嗪基、哌嗪-1-基、哌嗪-2-基、哌嗪-3-基、哌嗪-4-基、哌嗪-5-基、哌嗪-6-基、嗎啉基、嗎啉-2-基、嗎啉-3-基、嗎啉-4-基、嗎啉-5-基、嗎啉-6-基、硫嗎啉基、硫嗎啉-2-基、硫嗎啉-3-基、硫嗎啉-4-基、硫嗎啉-5-基、硫嗎啉-6-基、氧硫雜環己烷基、氧硫雜環己烷-2-基、氧硫雜環己烷-3-基、氧硫雜環己烷-5-基、氧硫雜環己烷-6-基、二噻烷基、二噻烷-2-基、二噻烷-3-基、二噻烷-5-基、二噻烷-6-基、二氧雜環戊基、二氧雜環戊-2-基、二氧雜環戊-4-基、二氧雜環戊-5-基、氧硫雜環己烷基、氧硫雜環己烷-2-基、氧硫雜環己烷-3-基、氧硫雜環己烷-4-基、氧硫雜環己烷-5-基、二硫雜環戊烷基、二硫雜環戊烷-2-基、二硫雜環戊烷-4-基、二硫雜環戊烷-5-基、吡唑啶基、吡唑啶-1-基、吡唑啶-2-基、吡唑啶-3-基、吡唑啶-4-基及吡唑啶-5-基。 如本文使用之術語「羥基」係指-OH基團。 如本文使用之術語「側氧基」係指=O基團。 如本文使用之術語「自體免疫疾病」或「自體免疫失調症」係指其中細胞不受控制地攻擊身體自身組織及器官(自體免疫性)，產生炎性反應及其他嚴重的症狀及疾病之疾病。自體免疫疾病之非限制性實例包括特發性血小板減少性紫癜、溶血性貧血、全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、類風濕性關節炎(RA)、多發性硬化症(MS)、全身性硬化症、由免疫介導或1型糖尿病、由免疫介導之腎小球腎炎、硬皮病、惡性貧血、禿髮、天皰瘡、尋常型天皰瘡、重症肌無力、炎性腸疾病、克隆氏症(Crohn’s disease)、葛瑞夫茲氏症(Graves’ disease)、牛皮癬、自體免疫性甲狀腺疾病、橋本氏病(Hashimoto’s disease)、橋本氏甲狀腺炎、多肌炎、皮肌炎、CREST症候群、古德帕斯丘症候群(Goodpasture's syndrome)、混合型結締組織疾病重症肌無力假麻痺、眼球震顫、晶狀體基因葡萄膜炎(phakogene uveitis)、慢性侵襲性肝炎、原發性膽汁性肝硬化、自體免疫性溶血性貧血、維洛夫疾病(Werlof disease)、尋常型白癜風、***(Behcet’s disease)、膠原病、葡萄膜炎、休格倫症候群、自體免疫性心肌炎、自體免疫性肝病、自體免疫性胃炎、天皰瘡、格巴二氏症候群(Guillain-Barre syndrome)、動脈粥樣硬化、炎症性腸病、強直性脊柱炎、特發性血小板減少症、結節性多動脈炎、原發性膽管硬化、結節病、硬化性膽管炎、多發性大動脈炎(Takayasu’s arteritis)、顳動脈炎、韋格納肉芽腫病(Wegener’s granulomatosis)及HTLV-1相關之脊髓病。 如本文使用之術語「組合」或「醫藥組合」意指源自混合或組合至少一種活性成分且包括活性成分之固定及非固定組合之產品。術語「固定組合」意指活性成分((以實例說明之)本發明之化合物及一或多種額外之治療劑)係以單一實體或劑量之形式向個體同時投與。術語「非固定組合」意指活性成分((以實例說明之)本發明之化合物及一或多種額外之治療劑)係作為獨立實體向個體同時、兼而或順序投與而無特定時間限制，其中此投與在個體之體內提供治療有效濃度之活性成分。後者亦適用於混合物治療，例如，3或多種活性成分之投與。 如本文使用之術語「組合物」或「醫藥組合物」係指本發明之化合物與至少一種及視需要多於一種其他醫藥上可接受之化學組分(諸如載劑、穩定劑、稀釋劑、分散劑、懸浮劑、增稠劑及/或賦形劑)之混合物。 如本文使用，術語「抑制」係指給定病症、症狀或失調症或疾病之減少或抑制或生物活性或過程之基線活性之顯著減小。 如本文使用之術語「光學異構物」或「立體異構物」係指針對本發明之給定化合物可存在之各種立體異構構形中之任何一者且包括幾何異構物。應瞭解取代基可連接於碳原子之對掌性中心。術語「對掌性」係指與其鏡像伴侶具有不可重疊之性質之分子，而術語「非對掌性」係指與其鏡像伴侶可重疊之分子。因此，本發明包括該化合物之對映異構物、非對映異構物或外消旋物。「對映異構物」係立體異構物對，其等彼此互為不可重疊之鏡像。對映異構物對之1:1混合物係「外消旋」混合物。該術語視需要適用於指定外消旋混合物。「非對映異構物」係具有至少兩個非對稱原子，但其等彼此非鏡像之立體異構物。絕對立體化學係根據Cahn-lngold-Prelog R-S系統規定。當化合物係純對映異構物時，於各對掌性碳處之立體化學可由R或S規定。絕對構形未知之經解析之化合物可指定為(+)或(-)，此取決於其等在鈉D線之波長下旋轉平面偏振光之方向(右旋或左旋)。本文描述之某些化合物含有一或多個非對稱中心或軸且可因此產生對映異構物、非對映異構物及其他立體異構形式，其等就絕對立體化學而言可定義為(R)-或(S)-。 如本文使用之術語「醫藥上可接受之載劑」包括任何及所有溶劑、分散介質、包衣、表面活性劑、抗氧化劑、防腐劑(例如，抗菌劑、抗真菌劑)、等滲劑、吸收延遲劑、鹽、防腐劑、藥物穩定劑、黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調味劑、染料及類似物及其組合，如熟習此項技術者已知(參見，例如，Remington's Pharmaceutical Sciences，第18版，Mack Printing Company，1990，第1289至1329頁)。除在任何習知載劑與活性成分不相容之情況下外，亦預測其於治療或醫藥組合物中之用途。 如本文使用之術語「醫藥上可接受之鹽」係指不消除本發明之化合物之生物活性及性質，且對所投與之個體不引起顯著刺激之鹽。 如本文使用之術語「個體」包含哺乳動物及非哺乳動物。哺乳動物之實例包括(但不限於)人類、黑猩猩、猿、猴、牛、馬、綿羊、山羊、豬、兔、狗、貓、大鼠、小鼠、豚鼠及類似物。非哺乳動物之實例包括(但不限於)鳥、魚及類似物。通常，該個體係人類，且可係已診斷為需針對與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯或與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及任何組合之活性相關聯之疾病或失調症之治療之人類。 術語「有此治療需要之個體」係指將自此治療在生物學上、醫藥上或品質生活方面獲益之個體。 如本文使用之術語「治療有效量」係指將引起個體之生物或醫藥反應 (例如，酶或蛋白質活性之減小或抑制或減輕症狀、緩解病症、減緩或延遲疾病進展或預防疾病等)之本發明之化合物之量。在一項非限制性實施例中，術語「治療有效量」係指本發明之化合物在向個體投與時有效(1)至少部分減輕、抑制、預防及/或減輕(i)由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)介導或由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合介導或(ii)與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)相關聯或與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合相關聯或(iii)由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性(正常或異常)表徵之病症或失調症或疾病；(2)減小或抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性；或(3)減少或抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之表現之量。在另一非限制性實施例中，術語「治療有效量」係指本文提供之化合物在向細胞或組織或非細胞生物材料或培養基投與時有效(至少部分)減小或抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)及其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性或抑制胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合之活性之量。 如本文使用之術語「TLR7抑制劑」、「TLR7拮抗物」、「TLR7之抑制劑」或「TLR7之抑制劑」係指抑制類鐸受體7 (TLR7)之本發明之化合物。本發明之化合物抑制TLR7下游之I型干擾素及促炎細胞介素兩者。 如本文使用之術語「TLR8抑制劑」、「TLR8拮抗物」、「TLR8之抑制劑」或「TLR8之抑制劑」係指抑制類鐸受體8 (TLR8)之本發明之化合物。 如本文使用之術語「TLR7及TLR8抑制劑」、「TLR7及TLR8拮抗物」、「TLR7及TLR8之抑制劑」或「TLR7及TLR8之抑制劑」係指抑制類鐸受體7 (TLR7)及類鐸受體8 (TLR8)之本發明之化合物。本發明之化合物抑制TLR7及TLR8傳訊中TLR7下游之I型干擾素及NF-KB下游之促炎細胞介素。「TLR7及TLR8抑制劑」或「TLR7及TLR8拮抗物」亦可由術語「TLR7/8拮抗物」表示。 如本文使用之術語「TLR7、TLR8及TLR9抑制劑」、「TLR7、TLR8及TLR9拮抗物」、「TLR7、TLR8及TLR9之抑制劑」或「TLR7、TLR8及TLR9之抑制劑」係指抑制類鐸受體7 (TLR7)、類鐸受體8 (TLR8)及類鐸受體9 (TLR9)之本發明之化合物。本發明之化合物抑制TLR7及TLR8傳訊中TLR7下游之I型干擾素及NF-KB下游之促炎細胞介素。「TLR7及TLR8及TLR9抑制劑」或「TLR7及TLR8及TLR9拮抗物」亦可由術語「TLR7/8/9拮抗物」表示。 在一項實施例中，任何疾病或失調症之術語「治療」係指減輕該疾病或失調症(即，減緩或阻止或減少該疾病或其臨床症狀中之至少一者之發展)。在另一實施例中，「治療」係指緩解或減輕至少一個物理參數，該等參數包括彼等無法由病患識別者。在又另一實施例中，「治療」係指物理上(例如，可識別症狀之穩定化)、生理上(例如，物理參數之穩定化)或兩者上調節該疾病或失調症。在又另一實施例中，「治療」係指預防或延遲該疾病或失調症之發病或發展或進展。 本文提供之化合物名稱係使用ChemDraw Ultra version 12.0 (CambridgeSoft®)或JChem version 5.3.1 (ChemAxon)獲得。 除非本文另有規定，否則術語「本發明之化合物(compounds of the present invention)」、「本發明之化合物(compounds of the invention)」或「本文提供之化合物」係指式(A)、式(I)、式(II)及其子式化合物(諸如式(Ia至Ip)及式(IIa至IIk)化合物)及醫藥上可接受之鹽、立體異構物(包括非對映異構物及對映異構物)、旋轉異構物、互變異構物及經同位素標記之化合物(包括氘取代)及固有形成之部分。 如本文使用，除非本文另有指示或與本文明顯相悖，否則本發明之內文(尤其隨附申請專利範圍之內文)中使用之術語「一」、「一個」、「該」及類似術語應視為涵蓋單數及複數兩者。本發明之化合物 本發明之化合物係具有式(A)結構之化合物或其醫藥上可接受之鹽：式(A) 其中， RA 係、、、、、、、、、或； L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -、-XCH2 -或-CH2 X-； X係-CH2 -或O； R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、-NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 、-NHC(=O)(CH2 )n NR9 S(=O)2 R5 、、、8-氧雜-3-氮雜雙環[3.2.1]辛基、具有獨立地選自N、O及S之1至3個環成員之5至6員雜芳基及具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代； R2 係H、C1 -C6 烷基、C1 -C6 鹵烷基或經1至2個R15 基團取代之C1 -C6 烷基； R3 係H、C1 -C6 烷基、-CD3 或經1至2個R10 基團取代之苄基； R4 係H、NH2 、C1 -C6 烷基、鹵基或經0至2個R18 基團取代之苯基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基、氧雜-3-氮雜雙環[3.2.1]辛烷或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R7 係獨立地選自C1 -C6 烷基、鹵基、羥基、側氧基及經1至3個-OH取代之C1 -C6 烷基； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R10 係C1 -C6 烷氧基或C3 -C6 環烷基； R11 係未經取代或經1至3個C1 -C6 烷基取代之C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； R15 係-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CHR9 )n R6 、-N(R6 )2 、-N(CD3 )2 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 ； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基或及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 本發明之化合物之某些態樣及實例係提供於額外之枚舉型實施例之下列列表中。將認知各實施例中規定之特徵可與其他規定特徵組合以提供本發明之其他實施例。 實施例1：具有式(A)結構之化合物係具有式(I)或式(II)結構之化合物或其醫藥上可接受之鹽： 式(I) 式(II)。 其中Y1 、Y2 、Y3 、L、R1 、R2 及RA 係如本文針對式(A)化合物定義。 實施例2：具有式(A)或式(I)結構之化合物係具有式(Ia)、式(Ib)、式(Ic)、式(Id)、 式(Ie)、式(If)、式(Ig)、式(Ih)、式(Ii)、式(Ij)或式(Ik)結構之化合物或其醫藥上可接受之鹽：、、 式(Ia) 式(Ib)、式(Ic) 式(Id)、式(Ie) 式(If)、式(Ig) 式(Ih)、式(Ii) 式(Ij)， 式(Ik) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 、R14 及R18 係如本文針對式(A)化合物定義。 實施例3：具有式(A)或式(I)結構之化合物係具有式(Ia)或式(Ig)結構之化合物或其醫藥上可接受之鹽： 式(Ia) 式(Ig) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R13 係如本文針對式(A)化合物定義。 實施例4：具有式(A)或式(I)結構之化合物係具有式(Ib)、式(Ic)或式(Id)結構之化合物或其醫藥上可接受之鹽：、式(Ib) 式(Ic)式(Id) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R13 係如本文針對式(A)化合物定義。 實施例5：具有式(A)或式(I)結構之化合物係具有式(Ie)或式(Ih)結構之化合物或其醫藥上可接受之鹽：、式(Ie) 式(Ih) 其中Y1 、Y2 、Y3 、L、R1 、R2 及R3 係如本文針對式(A)化合物定義。 實施例6：具有式(A)或式(I)結構之化合物係具有式(If)結構之化合物或其醫藥上可接受之鹽：式(If) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R14 係如本文針對式(A)化合物定義。 實施例7：具有式(A)或式(I)結構之化合物係具有式(Ii)結構之化合物或其醫藥上可接受之鹽：式(Ii) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R4 及各R13 係如本文針對式(A)化合物定義。 實施例8：具有式(A)或式(I)結構之化合物係具有式(Ij)或式(Ik)結構之化合物或其醫藥上可接受之鹽： 式(Ij) 式(Ik) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 及R18 係如本文針對式(A)化合物定義。 實施例9：具有式(A)或式(I)結構之化合物係具有式(Im)結構之化合物或其醫藥上可接受之鹽：式(Im) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 及R4 係如本文針對式(A)化合物定義。 實施例10：具有式(A)或式(I)結構之化合物係具有式(In)結構之化合物或其醫藥上可接受之鹽：式(In) 其中Y1 、X、L、R1 、R2 、R3 及R4 係如本文針對式(A)化合物定義。 實施例11：具有式(A)或式(I)結構之化合物係具有式(Io)結構之化合物或其醫藥上可接受之鹽：式(Io) 其中L、R1 、R2 、R3 及R4 係如本文針對式(A)化合物定義。 實施例12：具有式(A)或式(I)結構之化合物係具有式(Ip)結構之化合物或其醫藥上可接受之鹽：式(Ip) 其中R1 係如本文針對式(A)化合物定義。 實施例13：具有式(A)或式(II)結構之化合物係具有式(IIa)、式(IIb)、式(IIc)、式(IId)、式(IIe)、式(IIf)、式(IIg)、式(IIh)、式(IIi)、式(IIj)或式(IIk)結構之化合物或其醫藥上可接受之鹽：、、 式(IIa) 式(IIb)、式(IIc) 式(IId)、式(IIe) 式(IIf)、式(IIg) 式(IIh)、式(IIi) 式(IIj)， 式(IIk) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 、R14 及R18 係如本文針對式(A)化合物定義。 實施例14：具有式(A)或式(II)結構之化合物係具有式(IIa)或式(IIg)結構之化合物或其醫藥上可接受之鹽： 式(IIa) 式(IIg) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R13 係如本文針對式(A)化合物定義。 實施例15：具有式(A)或式(II)結構之化合物係具有式(IIb)、式(IIc)或式(IId)結構之化合物或其醫藥上可接受之鹽：、式(IIb) 式(IIc)式(IId) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R13 係如本文針對式(A)化合物定義。 實施例16：具有式(A)或式(II)結構之化合物係具有式(IIe)或式(IIh)結構之化合物或其醫藥上可接受之鹽：、式(IIe) 式(IIh) 其中Y1 、Y2 、Y3 、L、R1 、R2 及R3 係如本文針對式(A)化合物定義。 實施例17：具有式(A)或式(II)結構之化合物係具有式(IIf)結構之化合物或其醫藥上可接受之鹽：式(IIf) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 及R14 係如本文針對式(A)化合物定義。 實施例18：具有式(A)或式(II)結構之化合物係具有式(IIi)結構之化合物或其醫藥上可接受之鹽：式(IIi) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R4 及各R13 係如本文針對式(A)化合物定義。 實施例19：具有式(A)或式(II)結構之化合物係具有式(IIj)或式(IIk)結構之化合物或其醫藥上可接受之鹽： 式(IIj) 式(IIk) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 及R18 係如本文針對式(A)化合物定義。 實施例20：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、 -NHC(=O)OR9 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NR9 C(=O)OR11 、-NHC(=O)(CH2 )n N(CD3 )2 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 或-NHC(=O)(CH2 )n NR9 S(=O)2 R5 ； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R11 係未經取代或經1至3個C1 -C6 烷基取代之C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基或及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例21：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係-NH(CH2 )n C(=O)R6 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NH(C(R9 )2 )n R10 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 ； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R10 係C1 -C6 烷氧基或C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例22：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )或-N(R6 )2 ； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例23：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、-NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 或-NHC(=O)(CH2 )n NR9 S(=O)2 R5 。 實施例24：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、-NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 或-NHC(=O)(CH2 )n NR9 S(=O)2 R5 。 實施例25：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、-NHC(=O)OR9 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NR9 C(=O)OR11 、-NHC(=O)(CH2 )n N(CD3 )2 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 或-NHC(=O)(CH2 )n NR9 S(=O)2 R5 。 實施例26：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 。 實施例27：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 或-NHR8 。 實施例28：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHR6 、-NH2 、-N(R5 )2 、-NHR5 或-NHR8 。 實施例29：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NH(CH2 )n C(=O)R6 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 。 實施例30：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )m N(R5 )2 、-NHR6 或-NH2 。 實施例31：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R1 係-NHC(=O)R6 、-NHC(=O)(CHR9 )n R6 、-NH(CHR9 )n C(=O)R6 或-NHR6 ； 實施例32：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NH(CH2 )n C(=O)R6 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NH(C(R9 )2 )n R10 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 。 實施例33：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )或-N(R6 )2 。 實施例34：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR8 、8-氧雜-3-氮雜雙環[3.2.1]辛基、或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代。 實施例35：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NH(CHR9 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、8-氧雜-3-氮雜雙環[3.2.1]辛基、或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代。 實施例36：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係、、-OR9 、8-氧雜-3-氮雜雙環[3.2.1]辛基、具有獨立地選自N、O及S之1至3個環成員之5至6員雜芳基或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R7 係獨立地選自C1 -C6 烷基、鹵基、羥基、側氧基及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例37：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係8-氧雜-3-氮雜雙環[3.2.1]辛基、、具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其經1至2個R7 基團取代，其中各R7 係獨立地選自C1 -C6 烷基、羥基及側氧基。 實施例38：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其經1至2個R7 基團取代，其中各R7 係獨立地選自C1 -C6 烷基、羥基及側氧基。 實施例39：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係氮雜環丁烷基、吡咯啶基、嗎啉基、哌啶基、哌嗪基或咪唑基， 或 R1 係氮雜環丁烷基、吡咯啶基、嗎啉基、哌啶基、哌嗪基或咪唑基，其經1至2個R7 基團取代，其中且各R7 係獨立地選自C1 -C6 烷基、羥基及側氧基。 實施例40：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基、8-氧雜-3-氮雜雙環[3.2.1]辛基、或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其經1至2個R7 基團取代。 實施例41：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代。 實施例42：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R1 係氮雜環丁烷基、吡咯啶基、嗎啉基、哌啶基或哌嗪基。 實施例43：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R1 係氮雜環丁烷基、吡咯啶基、嗎啉基、哌啶基或哌嗪基，其等中之各者係經1至2個R7 基團取代。 實施例44：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R1 係8-氧雜-3-氮雜雙環[3.2.1]辛基或。 實施例45：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係C3 -C6 環烷基或具有獨立地選自N、NH及O之1至2個環成員之未經取代之4至6員雜環烷基。 實施例46：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係具有獨立地選自N、NH及O之1至2個環成員之4至6員雜環烷基。 實施例47：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基。 實施例48：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R6 係具有獨立地選自N、NH及O之1至2個環成員之4至6員雜環烷基，其經1至2個R12 基團取代，其中各R12 係獨立地選自C1 -C6 烷基、羥基及經1至3個-OH取代之C1 -C6 烷基。 實施例49：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R6 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其經1至2個R12 個基團取代，其中各R12 係獨立地選自C1 -C6 烷基、羥基及經1至3個-OH取代之C1 -C6 烷基。 實施例50：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係C3 -C6 環烷基。 實施例51：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係環丁基、氧雜環丁烷基、哌啶基、吡咯啶基、嗎啉基或氮雜環丁烷基。 實施例52：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R6 係環丁基、氧雜環丁烷基、哌啶基、吡咯啶基、嗎啉基或氮雜環丁烷基，其等中之各者係經1至2個R12 基團取代，其中各R12 係獨立地選自C1 -C6 烷基、羥基及經1至3個-OH取代之C1 -C6 烷基。 實施例53：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係氧雜環丁烷基、哌啶基、吡咯啶基、嗎啉基或氮雜環丁烷基。 實施例54：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R6 係環丁基。 實施例55：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -；Y1 係-CH2 CH2 -；Y2 係-CH2 CH2 -；Y3 係-XCH2 -；及X係-CH2 -或O。 實施例56：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -；Y1 係-CH2 CH2 -；Y2 係-CH2 CH2 -；Y3 係-XCH2 -；及X係-CH2 -。 實施例57：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -或-CH2 CH2 -；Y1 係-CH2 -或-CH2 CH2 -；Y2 係-CH2 -或-CH2 CH2 -；Y3 係-CH2 -或-XCH2 -；及X係-CH2 -或O。 實施例58：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -；Y1 係-CH2 -；Y2 係-CH2 -；Y3 係-CH2 -；及X係-CH2 -。 實施例59：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -；Y1 係-CH2 -；Y2 係-CH2 CH2 -；Y3 係-XCH2 -；及X係-CH2 -或O。 實施例60：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -；Y1 係-CH2 -；Y2 係-CH2 CH2 -；Y3 係-XCH2 -；及X係-CH2 -。 實施例61：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R2 係C1 -C6 烷基；R3 係C1 -C6 烷基及R4 係C1 -C6 烷基。 實施例62：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R2 係甲基；R3 係甲基及R4 係甲基。 實施例63：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基。 實施例64：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R2 係H或C1 -C6 烷基。 實施例65：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R3 係H、C1 -C6 烷基或-CD3 。 實施例66：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R3 係H或C1 -C6 烷基。 實施例67：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R4 係H、NH2 、C1 -C6 烷基或鹵基。 實施例68：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R4 係H、NH2 或C1 -C6 烷基。 實施例69：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R4 係H或C1 -C6 烷基。 實施例70：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R5 係獨立地選自C1 -C6 烷基及-(CH2 )n OR9 。 實施例71：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R5 係獨立地選自C1 -C6 烷基及-CD3 。 實施例72：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R5 係獨立地選自甲基、乙基、異丙基、第三丁基、-CD3 、-CH2 CH2 OCH2 CH3 及-CH2 CH2 OCH3 。 實施例73：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R7 係獨立地選自甲基、乙基及側氧基。 實施例74：式(I)、式(Ia)、式(Ib)及式(Ic)化合物，其中，各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基。 實施例75：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R8 係獨立地選自-CH2 CHF2 、-CH2 CF3 、-CH(CH3 )CH2 OH、-CH2 C(CH3 )2 OCH3 、-CH2 CH2 OCH3 、CH2 CH2 OCH2 CH3 及-CH2 C(CH3 )2 OH。 實施例76：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R9 係獨立地選自H及C1 -C6 烷基。 實施例77：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，各R9 係獨立地選自H、甲基及乙基。 實施例78：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R13 係H。 實施例79：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R13 係C1 -C6 烷基。 實施例80：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R14 係H。 實施例81：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，R13 係H及R14 係H。 實施例82：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，m係1、2或3及n係1、2、3或4。 實施例83：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，m係1、2或3。 實施例84：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中，n係1、2、3或4。 實施例85：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NH(CHR9 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、8-氧雜-3-氮雜雙環[3.2.1]辛基、或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代； 各R5 係獨立地選自C1 -C6 烷基及-(CH2 )n OR9 ； R6 係具有獨立地選自N、NH及O之1至2個環成員之未經取代之4至6員雜環烷基或C3 -C6 環烷基； 各R7 係獨立地選自C1 -C6 烷基、羥基及側氧基； 各R8 係獨立地選自C1 -C6 鹵烷基及-(C(R9 )2 )n OR9 ； 各R9 係獨立地選自H及C1 -C6 烷基； R16 係C1 -C6 烷基； m係1、2、3、4、5或6 及 n係1、2、3、4、5或6。 實施例86：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR8 、8-氧雜-3-氮雜雙環[3.2.1]辛基、或具有獨立地選自N、NH、NR16 或O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代； 各R5 係獨立地選自C1 -C6 烷基及-(CH2 )n OR9 ； R6 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基或C3 -C6 環烷基； 各R7 係獨立地選自C1 -C6 烷基、羥基及側氧基； 各R8 係獨立地選自C1 -C6 烷基、C1 -C6 鹵烷基及-(C(R9 )2 )n OR9 ； 各R9 係獨立地選自H及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例87：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 或-NHR8 ； 各R5 係獨立地選自C1 -C6 烷基及-(CH2 )n OR9 ； R6 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基或C3 -C6 環烷基； 各R8 係獨立地選自C1 -C6 烷基、C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例88：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH2 、-N(R5 )2 或-NHR8 ； 各R5 係獨立地選自C1 -C6 烷基及-(CH2 )n OR9 ； 各R8 係獨立地選自C1 -C6 烷基、C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例89：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CHR9 )n R6 、-NH(CHR9 )n C(=O)R6 或-NHR6 ； R6 係具有獨立地選自N、NH、NR16 及O之1至2個環成員之未經取代之4至6員雜環烷基或C3 -C6 環烷基； 各R9 係獨立地選自H及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。 實施例90：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物，其中， L係-CH2 -； Y1 係-CH2 CH2 -； Y2 係-CH2 CH2 -； Y3 係-XCH2 -； X係-CH2 -； R1 係-NHC(=O)R6 ； R2 係C1 -C6 烷基； R3 係C1 -C6 烷基； R4 係C1 -C6 烷基； R6 係具有獨立地選自N、NH及O之1至2個環成員之未經取代之4至6員雜環烷基； R13 係H； R14 係H；及 各R17 係H。 實施例91：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物或其醫藥上可接受之鹽，選自： 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； 6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷； 4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(2-((4-胺基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(2-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-((5-(5-氯-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 1,6-二甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 1,3,5-三甲基-7-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[4,3-d]嘧啶； N-(2-甲氧基乙基)-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 2-(乙胺基)-N-(4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； 4-(4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 2-(乙胺基)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(氧雜環丁烷-3-基甲基)雙環[2.2.2]辛-1-胺； 3-(二甲基胺基)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)丙醯胺； 4-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-環丁基-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N,N-二環丁基-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 6-甲基-4-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 6-甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； (3-(((4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)甲基)氧雜環丁烷-3-基)甲醇； N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-甲醯胺； (S)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (S)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； (R)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； 3,6-二甲基-4-(3-甲基-1-((4-嗎啉基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)異噁唑并[5,4-d]嘧啶； 1,3,5-三甲基-7-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[4,3-d]嘧啶； 1,6-二甲基-4-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(三氘甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-(三氟甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-醇； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)甲磺醯胺； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)(甲基)胺甲酸第三丁酯； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸1-甲基環丙酯； 3-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[1.1.1]戊-1-胺； 4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-環丁基-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-異丙基雙環[2.2.2]辛-1-胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)丙-1-醇； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-乙基雙環[2.2.2]辛-1-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-7,7-二甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(2,2-二氟乙基)-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； -((3-甲基-5-(2-甲基喹啉-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 1-((4-(氮雜環丁烷-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-7,7-二甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺； 1,1-二氧化4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)硫嗎啉； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-醇； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-甲氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-乙氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-乙氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-N-甲基雙環[2.2.2]辛-1-胺； (3S,4R)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3,4-二醇； (S)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3-醇； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-N,N-二甲基乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-N-甲基氧雜環丁烷-3-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-異丙基-N-甲基雙環[2.2.2]辛-1-胺； N-環丁基-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺； (3S,4S)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3,4-二醇； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)-2-氧雜雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)吡啶-2-基)苄腈； 3-甲基-5-(2-苯基吡啶-4-基)-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 2-甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1,7-萘啶； 4-((5-(2-(4-氟苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(2-(2-氟-4-甲基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(2-(4-甲氧基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-(對甲苯基)吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(2-(5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)乙基)雙環[2.2.2]辛-1-胺； 4-((5-(2,8-二甲基-1,7-萘啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-6-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-([2,2'-聯吡啶]-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(哌啶-1-基)-2-氧雜雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(1-甲氧基丙-2-基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-乙基-N-甲基雙環[2.2.2]辛-1-胺； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基-2-氧雜雙環[2.2.2]辛-4-胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-1-(哌啶-1-基)乙酮； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(吡咯啶-1-基)乙醯胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基-2-甲基丙基)雙環[2.2.2]辛-1-胺； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-2-氧雜雙環[2.2.2]辛-4-胺； 4-((5-(2-氯-5,7-二氫呋喃并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-1-甲基哌嗪-2-酮； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(二甲基胺基)丙醯胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-1-(吡咯啶-1-基)乙酮； (R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲基嗎啉； 1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基哌嗪-2-酮； (S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲基嗎啉； (2S,6R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； (2S,6S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； N-(環丁基甲基)-1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； (2R,6R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(乙胺基)乙醯胺； 3-胺基-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)丙醯胺； 6-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)丙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)丙醯胺； 1-((4-(1H-咪唑-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； (1R,5S)-3-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-8-氧雜-3-氮雜雙環[3.2.1]辛烷； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基嗎啉-3-甲醯胺； 1-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-2-甲基丙-2-醇； 2-(乙胺基)-N-(4-((3-甲基-5-(5-甲基-1H-吡唑并[4,3-b]吡啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(乙胺基)丙醯胺； N-乙基-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-甲基嗎啉； (R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-甲基嗎啉； N-(2-甲氧基乙基)-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(乙基(甲基)胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-氟氮雜環丁烷-1-基)乙醯胺； 2-(雙(三氘甲基)胺基)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-羥基乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-羥基氮雜環丁烷-1-基)乙醯胺； (3-(((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)甲基)氧雜環丁烷-3-基)甲醇； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(N-甲基甲基磺醯胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(N-甲基乙醯胺基)乙醯胺； 4-((3-甲基-5-(6-甲基-1-(三氘甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (S)-N-(4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(甲胺基)丙醯胺； N-環丁基-1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； N-環丁基-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺，及 4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺。 實施例92：式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物或其醫藥上可接受之鹽，選自： N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺，及 6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷。 取決於起始材料及製程之選擇，本發明之化合物之某些實施例係以可能之異構物中之任何一者之形式存在或作為其混合物存在，例如作為純光學異構物或作為異構物混合物，諸如外消旋物及非對映異構物混合物存在，此取決於非對稱碳原子之數量。本發明意欲包括所有此等可能之異構物，包括外消旋混合物、非對映異構物混合物及光學純形式。光學活性(R)-及(S)-異構物可使用對掌性合成子或對掌性試劑製備或使用習知技術解析。若化合物含有雙鍵，則取代基可係E或Z構形。若化合物含有經雙取代之環烷基，則環烷基取代基可具有順式或反式構形。所有互變異構形式係意欲包括於本發明內。 在某些實施例中，式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物係藉由使式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物之游離鹼形式與化學計量量之適當之醫藥上可接受之有機酸或無機酸或合適之陰離子交換試劑反應製備成醫藥上可接受之酸加成鹽。本發明之某些化合物可藉由胺基或與其類似之基團之存在形成酸加成鹽。或者，式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物之鹽形式係使用起始材料或中間物之鹽製備。 醫藥上可接受之酸加成鹽可用無機酸及有機酸形成。用以形成式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物之某些醫藥上可接受之酸加成鹽之有機酸或無機酸包括(但不限於)乙酸、己二酸、抗壞血酸、天冬胺酸、苯甲酸、苯磺酸、碳酸、樟腦磺酸、癸酸、葉綠茶酸、檸檬酸、乙二磺酸、延胡索酸、D-甘油基-D-古洛糖酸、半乳糖二酸、半乳糖二酸/黏液酸、葡庚糖酸(gluceptic acid)、葡庚糖酸(glucoheptonoic acid)、葡糖酸、葡糖醛酸、麩胺酸、戊二酸、乙醇酸、馬尿酸、氫溴酸、鹽酸、氫碘酸、羥乙磺酸、乳酸、乳糖酸、月桂基硫酸、蘋果酸、順丁烯二酸、丙二酸、苦杏仁酸、甲磺酸(mesylic acid)、甲磺酸(methanesulfonic acid)、黏液酸、萘甲酸、1-羥基-2-萘甲酸、萘磺酸、2-萘磺酸、菸鹼酸、硝酸、十八酸、油酸、草酸、棕櫚酸、撲酸、磷酸、聚半乳糖醛酸、丙酸、癸二酸、硬酯酸、琥珀酸、磺基水楊酸、硫酸、酒石酸、對甲苯磺酸、三氟乙酸及三苯基乙酸。 額外之合適之酸加成鹽之列表可(例如)於「Remington's Pharmaceutical Sciences」，第20版，Mack Publishing Company, Easton, Pa., (1985)；及於Stahl及Wermuth之「Handbook of Pharmaceutical Salts: Properties, Selection, and Use」 (Wiley-VCH, Weinheim, Germany, 2002中找到。 本發明之化合物之鹽可藉由用合適之鹼性試劑處理轉化為游離化合物。 式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物之醫藥上可接受之酸加成鹽包括(但不限於)乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽(besylatye)、苯磺酸鹽(benzenesulfonate)、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、葉綠茶酸、檸檬酸鹽、乙二磺酸鹽(edisylate)、乙二磺酸鹽(ethanedisulfonate)、延胡索酸鹽、葡庚糖酸鹽(gluceptate)、葡庚糖酸鹽(glucoheptonate)、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽(napsylate)、2-萘磺酸鹽、萘磺酸鹽(naphthalenesulfonate)、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽(octadecanoate)、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽(stearate)、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯及昔萘酸鹽鹽形式。 在一項實施例中，本發明提供N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺，其以乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、乙二磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽、2-萘磺酸鹽、萘磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯或昔萘酸鹽鹽形式。 在一項實施例中，本發明提供N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺，其以乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、乙二磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽、2-萘磺酸鹽、萘磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯或昔萘酸鹽鹽形式。 在一項實施例中，本發明提供(S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺，其以乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、乙二磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽、2-萘磺酸鹽、萘磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯或昔萘酸鹽鹽形式。 在一項實施例中，本發明提供(R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺，其以乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、乙二磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽、2-萘磺酸鹽、萘磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯或昔萘酸鹽鹽形式。 在一項實施例中，本發明提供6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷，其以乙酸鹽、己二酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、苯磺酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、溴化物/氫溴酸鹽、樟腦磺酸鹽、右旋樟腦磺酸鹽、癸酸鹽、氯化物/鹽酸鹽、氯茶鹼鹽、檸檬酸鹽、乙二磺酸鹽、乙二磺酸鹽、延胡索酸鹽、葡庚糖酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸酯、麩胺酸鹽、戊二酸鹽、甘醇酸鹽、馬尿酸鹽、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽、甲磺酸鹽、硫酸甲酯、黏液酸鹽、萘甲酸鹽、萘磺酸鹽、2-萘磺酸鹽、萘磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、硬脂酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、半乳糖醛酸鹽、丙酸鹽、癸二酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽、三苯乙酸鹽、乙酸三苯酯或昔萘酸鹽鹽形式。 本文給定之任何式係亦意欲表示化合物之未經標記之形式及經同位素標記之形式。經同位素標記之化合物具有由本文給定之式繪示之結構，除一或多個原子係經具有經選擇之原子質量或質量數之原子置換外。可併入本發明之化合物內之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素，諸如分別2 H、3 H、11 C、13 C、14 C、15 N、18 F31 P、32 P、35 S、36 Cl、123 I、124 I、125 I。本發明包括如本文定義之各種經同位素標記之化合物，例如彼等其中存在放射性同位素諸如3 H及14 C者或彼等其中存在非放射性同位素諸如2 H及13 C者。此等經同位素標記之化合物適用於代謝研究(用14 C)、反應動力學研究(用例如2 H或3 H)、偵測或成像技術，諸如正電子發射斷層攝影術(PET)或單光子發射電腦斷層掃描攝影術(SPECT)，其包括藥物或受質組織分佈分析，或適用於病患之放射性治療。特定言之，18 F或經標記之化合物可尤其適用於PET或SPECT研究。經同位素標記之式(I)化合物可通常藉由熟習此項技術者已知的習知技術或藉由類似於彼等隨附實例及製備中描述者之方法使用適當之經同位素標記之試劑代替先前採用之未經同位素標記之試劑進行製備。 此外，以較重之同位素(特定言之氘(即，2 H或D))置換可提供因較大代謝穩定性所引起之某些治療優勢，例如經增加之活體內半衰期或經減小之劑量需求或治療指數之改善。應瞭解在本內文中將氘視為式(I)化合物之取代基。此較重之同位素(具體言之，氘)之濃度可由同位素濃化因子定義。如本文使用之術語「同位素濃化因子」意指指定同位素之同位素豐度與指定同位素之天然豐度間之比率。若本發明之化合物中之取代基經指示為氘，則此化合物針對各指定氘原子具有以下之同位素濃化因子：至少3500 (於各指定氘原子下併入52.5%氘)、至少4000 (併入60%氘)、至少4500 (併入67.5%氘)、至少5000 (併入75%氘)、至少5500 (併入82.5%氘)、至少6000 (併入90%氘)、至少6333.3 (併入95%氘)、至少6466.7 (併入97%氘)、至少6600 (併入99%氘)或至少6633.3 (併入99.5%氘)。 根據本發明之醫藥上可接受之溶劑合物包括彼等其中結晶化之溶劑可經同位素取代者，例如，D2 O、d6 -丙酮、d6 -DMSO。 含有可充當氫鍵之供體及/或受體之基團之本發明之化合物可與合適之共晶形成體形成共晶體。此等共晶體可藉由已知的共晶形成製程製備自本發明之化合物。此等製程包括在溶液中令本發明之化合物與共晶形成體在結晶條件下研磨、加熱、共升華、共熔或接觸並分離藉此形成之共晶體。合適之共晶形成體包括彼等WO 2004/078163中描述者。因此，本發明進一步提供包含式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物之共晶體。 除非本文另有指示或與內文明顯矛盾，否則本文描述之所有方法可以任何合適之順序進行。本文提供之任何及所有實例或例示性語言(例如，「諸如」)之使用僅意欲更適切地闡述本發明且非對本文另外主張之本發明之範圍進行限制。 本發明之化合物之任何非對稱原子(例如，碳或類似物)可以外消旋或對映體上富集之形式存在，例如，(R )-、(S )-或(R ,S )-構形。在某些實施例中，各非對稱原子在(R )-或(S )-構形下具有至少50%對映體過量、至少60%對映體過量、至少70%對映體過量、至少80%對映體過量、至少90%對映體過量、至少95%對映體過量或至少99%對映體過量。具有不飽和雙鍵之原子處之取代基可(若可能)以順式-(Z )-或反式-(E )-形式存在。 因此，如本文使用，本發明之化合物可以可能之異構物、旋轉異構物、阻轉異構物、互變異構物或其混合物中之任何一者之形式存在，例如，呈大體上純幾何(順式或反式)異構物、非對映異構物、光學異構物(對映體)、消旋物或其混合物。 異構物之任何所得混合物可基於成分之物理化學差異例如藉由層析術及/或分步結晶分離成純或大體上純幾何或光學異構物、非對映異構物、外消旋物。最終產物或中間物之任何所得外消旋物可藉由已知方法解析為光學對映體，例如，藉由分離用光學活性酸或鹼獲得之其非對映異構鹽，並釋放光學活性酸性或鹼性化合物。特定言之，鹼性部分可因此用以將本發明之化合物解析為其等光學對映體，例如，藉由分步結晶用光學活性酸(例如，酒石酸、二苯甲醯酒石酸、二乙醯酒石酸、二-O,O'-對甲苯甲醯基酒石酸、苦杏仁酸、蘋果酸或樟腦-10-磺酸)形成之鹽。外消旋產物亦可藉由對掌性層析術解析，例如，使用對掌性吸附劑之高壓液相層析術(HPLC)。 此外，本發明之化合物(包括其等鹽)亦可以其等水合物之形式獲得，或包括用於其等結晶化之其他溶劑。本發明之化合物可固有地或藉由設計與具有醫藥上可接受之溶劑(包括水)形成溶劑合物；因此，本發明意欲包含溶劑化及非溶劑化形式兩者。術語「溶劑合物」係指本發明之化合物(包括其醫藥上可接受之鹽)與一或多種溶劑分子之分子錯合物。此等溶劑分子係彼等常用於醫藥領域中之已知對接受者無害之溶劑分子，例如，水、乙醇及類似物。術語「水合物」係指其中該溶劑分子係水之錯合物。 本發明之化合物(包括其鹽、水合物及溶劑合物)可固有地或藉由設計形成多晶型物。用於製造式 (A) 及其子式化合物之方法 本文描述用於製備式(A)、式(I)、式(II)、式(Ia至Ip)及式(IIa至IIk)化合物之一般製程。在本文描述之反應中，反應性官能基(例如，羥基、胺基、亞胺基、硫基或羧基，其中此等在最終產物中係需要的)可經保護以避免其等在該等反應中非所需之參與。在本內文之範圍中，除非內文另有明確指示，否則僅非本發明之化合物之特定所需最終產物之成分之易於移除之基團被指定為「保護基」。官能基受此等保護基之保護、保護基本身及其等裂解反應係描述(例如)於標準參考著作中，諸如J. F. W. McOmie，「Protective Groups in Organic Chemistry」，Plenum Press, London及New York 1973，T. W. Greene及P. G. M. Wuts之「Protective Groups in Organic Synthesis」，第三版，Wiley, New York 1999，「The Peptides」；第3卷(編輯者：E. Gross及J. Meienhofer), Academic Press, London and New York 1981，「Methoden der organischen Chemie」 (Methods of Organic Chemistry), Houben Weyl，第4版，第15/I卷，Georg Thieme Verlag, Stuttgart 1974，H.-D. Jakubke及H. Jeschkeit, 「Aminosäuren, Peptide, Proteine」 (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim、Deerfield Beach及Basel 1982及Jochen Lehmann, 「Chemie der Kohlenhydrate: Monosaccharide und Derivate」 (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974。保護基之特徵在於其等可易於移除(即，不發生非所需之副反應)，例如，藉由溶劑分解、還原、光解或或者在生理條件下(例如，藉由酶裂解)移除。 式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物係藉由本文描述之方法且如實例中闡述製得。用以製造本發明之化合物之合成方案之非限制性實例係闡述於方案1及方案2中。 方案1闡述使用布赫瓦爾德-哈特維希胺化(Buchwald-Hartwig Amination)製造式(A)、式(I)及式(II)化合物之一項實施例，其中Pd催化受保護之胺中間物(Int-A)或受保護之胺中間物(Int-B)與雜芳基鹵化物中間物(Int-1)之交聯，接著去保護分別產生式(Ia)或式(IIa)化合物，其中R1 係NH2 。此外，烷化或醯化導致式(Ia)或式(IIa)化合物，其中R1 係如本文進一步定義。 方案1：布赫瓦爾德-哈特維希胺化在額外之實施例中，式(A)、式(I)及式(II)化合物可藉由用中間物Int-2、Int-3、Int-4、Int-5、Int-6、Int-7、Int-8、Int-9、Int-10或Int-11置換中間物(Int-1)獲得，分別得到式(Ic)、式(Ib)、式(If)、式(Ig)、式(Id)、式(Ie)、式(Ij)、式(Ii)、式(Ik)、式(Ih)、式(IIc)、式(IIb)、式(IIf)、式(IIg)、式(IId)、式(IIe)、式(IIj)、式(IIi)、式(IIk)及式(IIh)化合物。表1顯示替代中間物及個別產物， 其中TGA 係，TGB 係，X1 係Br、Cl、I或-SO3 CF3 ，及Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 及R14 係如本文定義。 表1 用於方案1之偶合反應中之Pd觸媒係選自Pd(II)觸媒，例如，雙(三鄰甲苯基膦)二氯化鈀(II)、雙(三鄰甲苯基膦)Pd(dba)2 、雙(三鄰甲苯基膦)Pd2 (dba)3 、PdCl2 (dppf)、(三鄰甲苯基膦)Pd(OAc)2 、Pd(OAc)2 及鈀環。 方案1之視需要之配體係選自二苯基膦基聯萘(BINAP)、二苯基膦二茂鐵(DPPF)、三鄰甲苯基膦(P(o-tol)3 )、三苯基膦(PPh3 )、三-第三丁基膦(P(t-Bu)3 )、2-(二環己基膦基)3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯(BrettPhos)、2-(二-第三丁基膦基)-2',4',6'-三異丙基-3,6-二甲氧基-1,1'-聯苯(t-BuBrettPhos)、2-二環己基膦基-2',4',6'-三異丙基聯苯(XPhos)、2-二-第三丁基膦基-2',4',6'-三異丙基聯苯(t-BuXPhos)、2-二環己基膦基-2',6'-二甲氧基聯苯(SPhos)、2-二環己基膦基-2',6'-二異丙氧基聯苯(RuPhos)、2-二環己基膦基-2'-(N,N-二甲基胺基)聯苯(DavePhos)、2'-(二-第三丁基膦基)-N,N-二甲基聯苯-2-胺、2-二-第三丁基膦基-2'-(N,N-二甲基胺基)聯苯(t-BuDavePhos)、2-二苯基膦基-2',6'-雙(二甲基胺基)-1,1'-聯苯(PhCPhos)、2-二(第三丁基)膦基-2',4',6'-三異丙基-3-甲氧基-6-甲基聯苯(RockPhos)、2-(二-金剛烷基膦基)-2',4',6'-三異丙基-3,6-二甲氧基-1,1’-聯苯(AdBrettPhos)、二-第三丁基(2',4',6'-三環己基-3,6-二甲氧基-[1,1'-聯苯]-2-基)膦、二-第三丁基(2',4',6'-三異丙基-3,4,5,6-四甲基-[1,1'-聯苯]-2-基)膦、4,5-雙(二苯基膦基)-9,9-二甲基呫噸(Xantphos)、2-(2-二環己基磷烷基苯基)-N1,N1,N3,N3-四甲基-苯-1,3-二胺(CPhos)、2'-(二苯基膦基)-N,N'-二甲基-(1,1'-聯苯)-2-胺(PhDavePhos)、2-{雙[3,5-雙(三氟甲基)苯基]膦基}-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯(JackiePhos)、(2-聯苯)二-第三丁基膦(JohnPhos)、(2-聯苯)-二環己基膦(CyJohnPhos)、2-二環己基膦基-2'-甲基聯苯(MePhos)、2-二-第三丁基膦基-2'-甲基)-1,1'-聯苯(t-BuMePhos)、2-二環己基膦基-2',6'-二甲氧基聯苯(SPhos)、2'-二環己基膦基-2,6-二甲氧基-1,1'-聯苯-3-磺酸鈉水合物(sSPhos)、外消旋-2-(二-第三丁基膦基)-1,1'-聯萘(TrixiePhos)、2-二-第三丁基膦基-3,4,5,6-四甲基-2',4',6'-三異丙基聯苯(Me4 t-BuXPhos)、2'-二環己基膦基-2,6-二-異丙基-4-磺酸根基-1,1'-聯苯水合物鈉鹽(XPhos-SO3 Na)、二-第三丁基(2',4',6'-三異丙基-4,5-二甲氧基-3,6-二甲基-[1,1'-聯苯]-2-基)膦及2'-(二環己基膦基)-N,N-二甲基-[1,1'-聯苯]-4-胺及三環己基膦(P(Cy)3)。 用於方案1之此等偶合反應中之鹼包括KOAc、NaOAc、K2 CO3 、Na2 CO3 、NaOEt、KOtBu、NaOtBu、LiHMDS、Cs2 CO3 、K3 PO4 、NaOH、KOH、tBuOH及NEt3 。此等偶合反應係在約100至180℃之範圍內之溫度下攪拌或係於微波爐中進行。另外，使用溶劑，例如，苯、甲苯、1,2-二甲氧基乙烷、乙腈、DCM、DMF、THF、二噁烷及N-甲基-2-吡咯啶酮。該反應可在惰性氣體(諸如氮或氬)下進行。 方案2闡述用於製造式(A)、式(I)及式(II)化合物之另一實施例，其使用鹼催化受保護之胺中間物(Int-A)或受保護之胺中間物(Int-B)與雜芳基鹵化物中間物(Int-1)之交聯，接著去保護分別產生式(Ia)或式(IIa)化合物，其中R1 係NH2 。進一步烷化或醯化導致式(Ia)或式(IIa)化合物，其中R1 係如本文進一步定義。 方案2：鹼催化交聯在額外之實施例中，式(A)、式(I)及式(II)化合物可藉由用中間物Int-2、Int-3、Int-4、Int-5、Int-6、Int-7、Int-8、Int-9、Int-10或Int-11置換中間物(Int-1)獲得，分別得到式(Ic)、式(Ib)、式(If)、式(Ig)、式(Id)、式(Ie)、式(Ij)、式(Ii)、式(Ik)、式(Ih)、式(IIc)、式(IIb)、式(IIf)、式(IIg)、式(IId)、式(IIe)、式(IIj)、式(IIi)、式(IIk)及式(IIh)化合物。表2顯示替代中間物及個別產物， 其中TGA 係，TGB 係，X1 係Br、Cl、I或-SO3 CF3 ，及Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 及R14 係如本文定義。 表2 用於方案2之此等偶合反應中之鹼包括DIPEA、Cs2 CO3 、1,8-二氮雜雙環十一碳-7-烯(DBU)、NEt3 、K2 CO3 、CaCO3 、Na2 CO3 、K3 PO4 、KF、KOAc、NaOEt、KOtBu及NaOH。此等偶合反應係在約80至180℃之範圍內之溫度下攪拌或係於微波爐中進行。用於方案(VII)及方案(VIII)之此等偶合反應中之溶劑包括H2 O、2-甲基-THF、2-甲基-THF/H2 O (1:1)、THF、MeOH、丁醇、第三丁醇、EtOAc、CAN、ACN、DMSO、 NMP、甲苯二甲基乙醯胺及DMF。該反應可在惰性氣體(諸如氮或氬)下進行。中間物 Int-A 及 Int-B 方案3闡述用於製造中間物Int-A及Int-B之實施例。 方案3。 方案4闡述用於製造中間物Int-A及Int-B之實施例。 方案4。 方案1至4中之胺保護基(Prot)係選自胺甲酸甲酯、胺甲酸9-茀基甲酯(Fmoc)、胺甲酸2,2,2-三氯乙酯(Troc)、胺甲酸第三丁酯(Boc)、胺甲酸2-(三甲基矽烷基)乙酯(Teoc)、胺甲酸烯丙酯(Alloc)、胺甲酸苄酯(Cbz)、亞苄基胺、對甲苯磺醯胺、三氟乙醯胺、乙醯胺、鄰苯二甲醯亞胺、苄胺、4-甲氧基苄胺(PMB)、烯丙胺及三苯甲胺。 本發明進一步包括本發明方法之任何變體，其中在其任何階段處可獲得之中間物產物係用作起始材料並進行剩餘步驟，或其中起始材料係在反應條件下當場形成，或其中反應組分係以其等鹽或光學純材料之形式使用。 本發明之化合物及中間物亦可根據熟習此項技術者通常已知的方法彼此轉化。 實例 本發明之化合物可如下列實例中顯示產生。下列實例意欲闡述本發明且不應視為限制本發明。溫度以攝氏度給定。若未另外提及，則所有蒸發均在減壓(通常在約15 mm Hg與100 mm Hg (= 20-133 mbar)之間)下進行。最終產物、中間物及起始材料之結構由標準分析方法(例如，微量分析及光譜特徵(例如，MS、IR、NMR))證實。本文使用之縮寫係彼等此項技術中常用之縮寫。 用以合成本發明之化合物之所有起始材料、建構組元、試劑、酸、鹼、脫水劑、溶劑及觸媒係購買獲得或可由一般技術者已知的有機合成方法產生或可由如本文描述之有機合成方法產生。縮寫： BH3 -DMS 硼烷二甲基硫醚 鹽水 濃氯化鈉水溶液 CPME 環戊基甲基醚 d 雙峰 dd 雙重雙峰 DCM 二氯甲烷 DMA 二甲基乙醯胺 DMAP 4-二甲基胺基吡啶 DME 1,2-二甲氧基乙烷 DMF N,N-二甲基甲醯胺 DMSO 二甲基亞碸 DIPEA 二異丙基乙胺 ESI 電噴霧離子化 ESIMS 電噴霧離子化質譜法 EtOAc 乙酸乙酯 EtOH 乙醇 eq 當量 HPLC 高壓液相層析術 hr 小時 hrs 小時 IPA 異丙醇 LC-MS或LC/MS 液相層析術及質譜法 MeOH 甲醇 MS 質譜法 m 多重態 mg 毫克 min 分鐘 mL 毫升 mm 毫米 mmol 毫莫耳 m/z 質荷比 nm 奈米 nm 奈莫耳 NMR 核磁共振 RT 滯留時間 rt 室溫 s 單重態 t 三重態 TFA 三氟乙酸 THF 四氫呋喃 UV 紫外線 µm 微米儀器法 LC-MS 方法 方法1：儀器包含具有1200sl HPLC泵及具有電噴霧(ESI)離子化之6100系列單四級桿質譜儀之Agilent LC/MS系統。在60℃下將樣品注射於Waters Acquity®HSS T3管柱C18 1.8 µm 2.1 x 50 mm上。梯度泵方法在整個2.25分鐘運行期間使用0.9 mL/分鐘之流動速率，以流動相A：於H2 O中之0.05% TFA，及流動相B：於乙腈中之0.035% TFA，10%B至100%B於1.36分鐘內。 方法2：3.5MIN_10TO100B：儀器包含具有1200sl HPLC泵及具有電噴霧(ESI)離子化之6100系列單四級桿質譜儀之Agilent LC/MS系統。在60℃下將樣品注射於Waters Acquity®HSS T3管柱C18 1.8 µm 2.1 x 50 mm上。梯度泵方法在整個2.25分鐘運行期間使用0.9 mL/分鐘之流動速率，以流動相A：於H2 O中之0.05% TFA，及流動相B：於乙腈中之0.035% TFA，10%B至100%B於1.36分鐘內。尾基 用以獲得本發明之化合物之尾基中間物顯示於下文及表4中，且下文亦描述其等各自合成。除非購買，否則用以獲得此等中間物之某些試劑之合成亦描述於下文中。購買之試劑 在各種尾基之合成中使用之某些中間物之合成 4-(三氟甲基)苯磺酸4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯(i-B1)之合成步驟1：在0℃下向4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛烷-1-羧酸(4.565g, 16.9 mmol)於THF (30 mL)中之溶液添加BH3 -DMS (5.15 mL, 3.0當量)。添加後，在室溫下將該反應進一步攪拌整夜。LC/MS指示該反應完成。該反應然後以滴加10%檸檬酸處理。水性處理後，接著ISCO純化(己烷/EtOAc)提供呈白色固體之(4-(羥甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。1 H NMR (400 MHz, DMSO-d6) δ 6.31 (s, 1H), 4.31 (t, J = 5.4 Hz, 1H), 2.99 (d, J = 5.4 Hz, 2H), 1.75 - 1.61 (m, 6H), 1.41 - 1.27 (m, 15H)。ESIMS (M+H+ ) 256.20。 步驟2：在室溫下向(4-(羥甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(1.021g, 4.0 mmol)及4-(三氟甲基)苯磺醯氯(1.566g, 6.4 mmol, 1.6當量)及DCM (10 mL)之混合物添加Et3 N (1.12 mL, 2.0當量)及DMAP (49mg, 0.1當量)。添加後，在室溫下將所得混合物進一步攪拌4小時。LC/MS指示該反應完成：主要兩個峰，m/z 408 (M+H+ -56)之產物峰及m/z 331之中間物峰。水性處理後，接著ISCO純化(己烷/EtOAc)以獲得呈白色固體之產物(i-B1)。1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 3.74 (s, 2H), 1.75 - 1.57 (m, 6H), 1.42 - 1.26 (m, 15H)。針對C21 H28 F3 NO5 S，ESIMS計算值(M+H+ ) 464.17，實測值408.00 (M+H+-56)。 4-(三氟甲基)苯磺酸(3-((第三丁氧基羰基)胺基)雙環[1.1.1]戊-1-基)甲酯(i-B2)之合成步驟1：在0℃下將LiAlH4 (83 mg, 2.188 mmol)溶解於THF (20 mL)中。將起始材料3-((第三丁氧基羰基)胺基)雙環[1.1.1]戊烷-1-羧酸甲酯(240 mg, 0.995 mmol)溶解於5 mL THF中，然後在0℃下添加至LiAlH4 溶液。該反應完成後，將反應混合物升溫至室溫並攪拌2小時。然後添加飽和Na2 SO4 溶液以淬滅該反應。過濾後移除溶劑以獲得用於下一步驟中之(3-(羥甲基)雙環[1.1.1]戊-1-基)胺甲酸第三丁酯。 步驟2：將(3-(羥甲基)雙環[1.1.1]戊-1-基)胺甲酸第三丁酯(180 mg, 0.844 mmol)、4-(三氟甲基)苯磺醯氯(206 mg, 0.844 mmol)及DIPEA (0.295 mL, 1.688 mmol)混合於DCM (5 mL)中並在25℃下將該反應混合物攪拌5小時。後處理及製備型LC-MS後，獲得用於下一步驟中之4-(三氟甲基)苯磺酸(3-((第三丁氧基羰基)胺基)雙環[1.1.1]戊-1-基)甲酯(i-B2)。ESIMS (M+H+ ) 422.1。 甲磺酸2-(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)乙酯(i-B3)之合成甲磺酸2-(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)乙酯(i-B3)係藉由將(287 mg, 1.065 mmol) (4-(2-羥乙基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯及三乙胺(216 mg, 2.131 mmol)混合於DCM (10.700 ml)中合成。在0℃下向此溶液添加甲磺醯氯(159 mg, 1.385 mmol)。添加後，在25℃下將所得混合物進一步攪拌18小時。LC-MS指示該反應完成。後處理(添加水及在DCM中萃取)後，有機層於MgSO4 上乾燥，過濾並在真空中濃縮。殘餘物無需進一步純化即可使用。1H NMR (400 MHz，氯仿-d) δ 4.23 (d, J = 6.0 Hz, 1H), 4.15 (t, J = 7.3 Hz, 2H), 2.92 (s, 3H), 1.78 - 1.71 (m, 6H), 1.55 - 1.50 (m, 2H), 1.50 - 1.42 (m, 6H), 1.35 (s, 9H)。ESIMS (M+H+ ) 348.2。 4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B4)之合成三氟甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B4)係藉由遵循用於甲磺酸2-(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)乙酯(i-B3)之合成方法製備，除使用4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚烷-1-羧酸甲酯置換(4-(2-羥乙基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯外。三氟甲磺酸4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B4)通常用作粗產物。 甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B5)之合成甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B5)係藉由遵循用於甲磺酸2-(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)乙酯(i-B3)之合成方法製備，除使用(4-(2-羥乙基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯置換(4-(2-羥乙基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯外。甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B5)通常用作粗產物。 4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)-2-氧雜雙環[2.2.2]辛-1-基)甲酯(i-B6)之合成4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)-2-氧雜雙環[2.2.2]辛-1-基)甲酯(i-B6)係藉由遵循用於4-(三氟甲基)苯磺酸(3-((第三丁氧基羰基)胺基)雙環[1.1.1]戊-1-基)甲酯(i-B2)之合成方法製備，除使用4-((第三丁氧基羰基)胺基)-2-氧雜雙環[2.2.2]辛烷-1-羧酸甲酯置換3-((第三丁氧基羰基)胺基)雙環[1.1.1]戊烷-1-羧酸甲酯外。RT (方法1)：1.84分鐘。針對C20 H26 F3 NO6 S (M+H+ )，ESIMS計算值465.5，實測值488.5 (M+ Na)。尾基之合成 (4-((4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG1)及(4-((4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG2)之合成步驟1：4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶(i-A0) (165 mg, 0.64 mmol)於甲醇(13.5 ml)中之溶液用DIPEA (2.91 ml, 16.66 mmol)處理，接著滴加氯甲酸苄酯(0.837 ml, 5.95 mmol)。將整個混合物攪拌18小時。LCMS顯示反應完成並在真空中濃縮該反應混合物。將殘餘物裝載於24 g矽膠管柱上，使用於DCM中之10%甲醇，以提供1,4,6,7-四氫-5H-吡唑并[4,3-c]吡啶-5-羧酸芐酯(針對C14 H15 N3 O2 (M+H+ )，MS計算值258.1，實測值258.1)。 步驟2：向含有1,4,6,7-四氫-5H-吡唑并[4,3-c]吡啶-5-羧酸芐酯(165 mg, 0.641 mmol)之20 mL閃爍小瓶添加4-(三氟甲基)苯磺酸4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯(i-B1) (446 mg, 0.962 mmol)、碳酸銫(418 mg, 1.28 mmol)及無水DMSO (3.2 mL)。將該混合物加熱至110℃，歷時18小時，然後稀釋於乙酸乙酯及水中。添加檸檬酸固體以中和pH。分層後，水層用乙酸乙酯反萃取三次。組合所有有機層，於硫酸鎂上乾燥並在真空中濃縮。殘餘物於40 g矽膠管柱上使用於DCM中之0至10%甲醇純化以提供兩種所需區域異構物之混合物(針對C20 H32 N4 O2 (M+H+ )，MS計算值361.3，實測值361.3)。 步驟3：向(TG1a)及(TG2a) (102 mg, 0.21 mmol)之混合物添加碳載鈀(0.0220 g, 0.0207 mmol)及乙醇(1 ml)。用氫(65 psi)將該混合物攪拌18小時；LCMS顯示~90%轉化率。過濾該混合物，用甲醇清洗並在真空中濃縮。將殘餘物裝載於40 g矽膠管柱上使用於DCM中之0至80%異丙醇以2%氨作為改質劑以提供直接用於分離步驟(下文)中之粗產物。 區域異構物分離 來自步驟2之56 mg (0.16 mmol) TG1及TG2係使用SFC層析術於21 x 250 mm氰基管柱(相：3 µm 4.6 x 50 mm，氰基，溶劑混合物：CO2 ：85%；1/1 v/v IPA:MeOH + 10 mm NH4 OAc -15%；製備條件：80 g/分鐘，88/6/6 CO2 /IPA/MeOH + 10 mm NH4OAc，~ 115 bar，2分鐘堆疊注射，5.25分鐘溶析時間)上分離以提供(4-((4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG1；峰2，RT 2.1分鐘，針對C21 H34 N4 O2 (M+H+)，ESIMS計算值361.3，實測值361.3)及(4-((4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG2；峰1，RT 1.71分鐘。針對C20 H32 N4 O2 (M+H+)，ESIMS計算值361.3，實測值361.3。 (4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3)及(4-((3-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG4)之合成步驟1：3-甲基-1H-吡唑并[4,3-c]吡啶(i-A1) (2.66 g, 19.98 mmol)於DMSO (80 ml)中之懸浮液用4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯(i-B1) (9.26 g, 19.98 mmol)及碳酸銫(13.02 g, 40.0 mmol)處理。將該混合物加熱至120℃歷時18小時以完成，然後冷卻至室溫並稀釋於乙酸乙酯及水中。分配後，有機層於硫酸鎂上乾燥並在真空中濃縮。殘餘物係於120 g矽膠管柱上使用於己烷中之0至80%乙酸乙酯及經延伸至於己烷中之80%乙酸乙酯純化以提供所需產物(4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(產物1)。梯度為經延伸之100%乙酸乙酯以溶析副產物(4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(產物2)。 產物1：RT (LCMS方法1)：1.510分鐘(質量–M+1- 371.2)，1 H NMR (400 MHz，甲醇-d4 ) δ 9.07 (s, 1H), 8.37 (d, J = 6.1 Hz, 1H), 7.60 (d, J = 6.2 Hz, 1H), 6.18 (寬s, 1H), 4.17 (s, 2H), 2.71 (s, 3H), 1.87 (dd, J = 10.0, 5.9 Hz, 6H), 1.66 (dd, J = 10.0, 5.9 Hz, 6H), 1.47 (s, 9H)。針對C21 H30 N4 O2 (M+H+)，ESIMS計算值371.5，實測值371.5。 產物2：RT (LCMS方法1)：1.47分鐘。針對C21 H30 N4 O2 (M+H+)，ESIMS計算值371.5，實測值371.5。 步驟2：產物1之氫化 (4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(產物1) (3.6267 g, 9.79 mmol)係使用H-cube系統氫化。一經完成，則濃縮反應溶液並裝載於120 g矽膠管柱上使用於DCM中之0至100% IPA以1%氨作為改質劑及然後經延伸至100% IPA以1%氨作為改質劑以溶析(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3)：1 H NMR (400 MHz, CD3 OD) δ 3.73 (s, 2H), 3.65 (s, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.12 (s, 3H), 1.87 - 1.74 (m, 6H), 1.61 - 1.47 (m, 6H), 1.39 (s, 9H)；針對C21 H34 N4 O2 (M+H+)，ESIMS計算值375.5，實測值375.5。 步驟2：產物2之氫化 (4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(1.011 g, 2.73 mmol)係使用H-cube系統氫化。一經完成，則濃縮反應溶液並裝載於24 g矽膠管柱上使用於DCM中之0至100% IPA以3% NH3 作為改質劑以產生(4-((3-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG4)。1 H NMR (400 MHz，甲醇-d4) δ 4.89 (d, J = 1.4 Hz, 1H), 3.75 (m 4H), 3.09 (t, J = 5.9 Hz, 2H), 2.72 (m, 2H), 2.15 (s, 3H), 1.79 (m, 6H), 1.54 (m, 6H), 1.40 (s, 9H)。針對C21 H34 N4 O2 (M+H+)，ESIMS計算值375.5，實測值375.5。 (4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯(TG5)之合成步驟1：在80℃下將3-甲基-1H-吡唑并[4,3-c]吡啶(i-A1) (133 mg, 1.0 mmol)、甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲酯(i-B5) (351 mg, 1.1 mmol)及Cs2 CO3 於DMSO (2 mL)中之混合物攪拌整夜。LC-MS顯示反應完成。然後將該反應混合物冷卻至室溫並用EtOAc/水稀釋。將層分離且有機層於Na2 SO4 上乾燥，然後濃縮。將粗產物添加(固體裝載)至40 g矽膠管柱並用於己烷中之0至100% EtOAc溶析。收集溶離份並濃縮以產生產物1，(4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯，及產物2，(4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯。 步驟2：使用H-Cube：90℃，20 bar H2 ，10% Pd/C，1 mL/分鐘流動速率將220 mg (0.617 mmol) (4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯轉化為所需產物(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯(TG5)。RT (LCMS方法2) 1.92分鐘。針對C20 H32 N4 O2 (M+H+ )，MS計算值361.5，實測值361.5。注意：產物2未經氫化。 1-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG6a)及2-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG7a)之合成將7,7-二甲基-1,4,6,7-四氫-5H-吡唑并[4,3-c]吡啶-5-羧酸第三丁酯(iA3) (120 mg, 0.477 mmol)、4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯(i-B1) (220 mg, 0.477 mmol)及Cs2 CO3 (156 mg, 0.477 mmol)混合於DMA (10 mL)中並在120℃下攪拌1小時。處理及製備型LC-MS後，獲得1-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG6a)及2-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯TG7a)。 4-((7,7-二甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(TG6)之合成將於二噁烷(4 N)中之1-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG6a) (70 mg, 0.143 mmol)及HCl (0.433 mL, 14.27 mmol)混合於MeOH (1 mL)中並在50℃下攪拌5小時。處理及製備型LC-MS後獲得4-((7,7-二甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(TG6)。 4-((7,7-二甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺(TG7)之合成將於二噁烷(4 N)中之2-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-7,7-二甲基-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG7a) (70 mg, 0.143 mmol)及HCl (0.433 mL, 14.27 mmol)混合於MeOH (1 mL)中並在50℃下攪拌5小時。處理及製備型LC-MS後獲得4-((7,7-二甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺(TG7)。 4-((3-(三氟甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(TG8)之合成步驟1：在80℃下將291 mg (1 mmol) 3-(三氟甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(i-A7)、510 mg (1.1 mmol)甲磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.1]庚-1-基)甲基甲烷磺基(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯及碳酸銫(652 mg, 2.0 mmol)於DMSO (5 mL)中之混合物攪拌整夜。冷卻至室溫後，該混合物用EtOAc/水稀釋。將層分離且水層用EtOAc萃取。經組合之有機層於Na2 SO4 上乾燥，然後濃縮以產生粗產物。將粗產物添加(固體裝載)至40 g矽膠管柱並用於己烷中之0至50% EtOAc溶析。收集溶離份並濃縮以產生所需產物，1-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-3-(三氟甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG8a)及痕量之2-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-3-(三氟甲基)-2,4,6,7-四氫-5H-吡唑并[4,3-c]吡啶-5-羧酸第三丁酯(TG9a)。TG8a：1H NMR (500 MHz，二氯甲烷-d2) δ 4.51 - 4.46 (m, 2H), 4.36 (s, 1H), 3.84 (s, 2H), 3.65 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 1.82 –1.73 (m, 6H), 1.59 - 1.52 (m, 6H), 1.46 (s, 9H), 1.38 (s, 9H)。MS (ES+): 529.4 (M+1)+。TG9a：方法1 (RT：2.07分鐘)，MS (ES+): 529.4 (M+1)+。 步驟2：向66 mg (0.125 mmol) 1-((4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲基)-3-(三氟甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-羧酸第三丁酯(TG8a)於二噁烷/MeOH (0.5 mL/0.3 mL)中之溶液添加HCl (於二噁烷中之4 M溶液，0.5 mL)。在室溫下將所得混合物攪拌2小時。將該反應混合物濃縮並凍乾以產生最終產物，呈HCl鹽之4-((3-(三氟甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(TG8)。方法1 (RT = 0.9分鐘)，MS (ES+): 329.2 (M+1)+。 甲基(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG10)之合成步驟1：在0℃下在N2 下向1.85 g (4.0 mmol) 4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)胺基)雙環[2.2.2]辛-1-基)甲酯(i-B1)於THF中之溶液添加208 mg (5.2 mmol) NaH。將該混合物升溫至室溫並攪拌30分鐘，然後冷卻回至0℃，然後滴加CH3 I (2.84 g, 20.0 mmol)。將所得混合物緩慢升溫至室溫並攪拌整夜。LC-MS顯示所需產物但反應未完成。添加額外之NaH (1.0當量)及CH3 I (5.0當量)並在室溫下將該反應混合物攪拌整夜。在0℃下藉由滴加2.0 mL 2-丙醇，然後滴加3.0 mL冷水淬滅該反應。然後將該混合物分配至EtOAc與水之間。將層分離且水層用EtOAc萃取。經組合之有機層於Na2 SO4 上乾燥，然後濃縮。將粗產物添加至80 g矽膠管柱並用於己烷中之0至30% EtOAc溶析。收集溶離份並濃縮以產生4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)(甲基)胺基)雙環[2.2.2]辛-1-基)甲酯。RT：3.1分鐘(方法2)。1H NMR (400 MHz，甲醇-d4) δ 8.11 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 3.73 (d, J = 1.9 Hz, 2H), 2.82 (s, 3H), 2.04 - 1.95 (m, 6H), 1.53 - 1.42 (m, 15H)。 步驟2：在80℃下將133 mg (1.0 mmol) 3-甲基-1H-吡唑并[4,3-c]吡啶、525 mg (1.1 mmol) 4-(三氟甲基)苯磺酸(4-((第三丁氧基羰基)(甲基)胺基)雙環[2.2.2]辛-1-基)甲酯及652 mg (2.0 mmol) Cs2 CO3 於DMSO中之混合物攪拌整夜。冷卻至室溫後，該混合物用EtOAc/水稀釋。將層分離且有機層於Na2 SO4 上乾燥，然後濃縮。將粗產物添加(固體裝載)至40 g矽膠管柱並用於己烷中之0至100% EtOAc溶析。收集溶離份並濃縮以產生作為主要產物(第一溶析)之甲基(4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯及作為次要或副產物(第二溶析)之甲基(4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。主要產物(甲基(4-((3-甲基-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯)：1 H NMR (400 MHz，甲醇-d4) δ 8.99 (d, J = 1.1 Hz, 1H), 8.29 (d, J = 6.2 Hz, 1H), 7.52 (dd, J = 6.2, 1.2 Hz, 1H), 4.10 - 4.07 (m, 2H), 2.80 (s, 3H),2.63 (s, 3H), 2.01 - 1.94 (m, 6H), 1.63 - 1.56 (m, 6H), 1.43 (s, 9H)。MS (ES+): 385.2 (M+1)+。次要或副產物(甲基(4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯)：1H NMR (400 MHz，甲醇-d4) δ 9.08 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.48 (dd, J = 6.3, 1.2 Hz, 1H), 4.19 (s, 2H), 2.81 (s, 3H), 2.77 (s,3H), 2.07 - 1.97 (m, 6H), 1.70 - 1.62 (m, 6H), 1.43 (s, 9H)。MS (ES+): 385.2 (M+1)+。 步驟3：使用H-Cube：100℃，15 bar H2 ，10% Pd/C，1 mL/分鐘流動速率，將甲基(4-((3-甲基-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(233 mg, 0.606 mmol)轉化為所需產物，甲基(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG10)。該產物無需純化即可直接使用。RT (方法2)：1.7分鐘，MS (ES+): 389.3 (M+1)+。表 4 ：額外之尾基 頭基 用以獲得本發明之化合物之頭基中間物顯示於表5中且下文顯示其等合成。除非購買，否則用以獲得此等中間物之某些試劑之合成亦描述於下文中。表 5 ：頭基 三氟甲磺酸1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基酯(HG7)之合成步驟1：在室溫下將1-(4-甲氧基苄基)-1H-吡唑-5-胺及乙醯乙酸乙酯於乙酸中之溶液攪拌整夜。在真空中濃縮反應及然後溶於DOWThermA中並在密封容器中加熱至230℃。該反應係在此溫度下維持40分鐘及然後冷卻至室溫。該反應係由管柱層析術(SiO2 , ISCO, 0-15% MeOH於二氯甲烷中)純化以提供直接用於下一步驟中之所需酚。 步驟2：在0℃下向1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-醇(1.895 g, 7.04 mmol)於DCM (100 mL, 3.33份)及THF (30 mL, 1份)之混合溶劑中之溶液添加三乙胺(7.36 mL, 52.8 mmol)，接著添加三氟甲磺酸酐(2.97 mL, 17.59 mmol)。在3小時內將該反應逐漸升溫至室溫。該反應係用飽和碳酸氫鈉溶液淬滅並用DCM萃取。有機相用鹽水清洗並乾燥。粗產物由矽膠層析術純化，用於己烷中之0%至50%乙酸乙酯溶析以產生三氟甲磺酸1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基酯(HG7)。RT (LC/MS方法2): 2.79分鐘。針對C16 H14 F3 N3 O4 (M+H+)，ESIMS計算值402.9，實測值402.9。 4-氯-2,8-二甲基-1,7-萘啶(HG10)之合成歷時30分鐘在室溫下向4-氯-2-甲基-1,7-萘啶(405 mg, 2.267 mmol)於THF (10 mL)中之溶液間歇性添加甲基溴化鎂(4.53 mL, 13.60 mmol，3 M於***中)。該反應自淺棕色變化至深綠色懸浮液。攪拌整夜後，該反應停止及然後藉由添加飽和NH4 Cl (10 mL)淬滅，用EtOAc (3 x 25 mL)萃取。EtOAc用鹽水(5 mL)清洗，於Na2 SO4 上乾燥並蒸發以產生所需粗產物4-氯-2,8-二甲基-7,8-二氫-1,7-萘啶。MS 195.1 (M+1)，RT (LC/MS方法1) 0.94分鐘。含有副產物MS 193.1 (M+1)，RT (LC/MS方法1) 0.85分鐘。該粗產物無需純化即可用於下一步驟中。 將來自上文之粗4-氯-2,8-二甲基-7,8-二氫-1,7-萘啶(440 mg, 2.260 mmol)溶解於DCM (20 mL)中。添加DDQ (513 mg, 2.260 mmol)。將該混合物超聲處理2分鐘。LCMS顯示反應完成。該混合物用EtOAc (50 mL)稀釋，濾過矽藻土濾餅。該濾餅用EtOAc (50 mL)清洗。蒸發有機物以產生黑色殘餘物。粗產物由急速層析術(EtOAc:hex/0至100%)純化產生4-氯-2,8-二甲基-1,7-萘啶(HG10): MS 193.1 (M+1)，RT 0.82分鐘。(方法1)。 4-氯-1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶(HG13)之合成步驟1：使2.5 g 1-乙基-1H-吡唑-5-胺(22.5 mmol)、23.4 g (180 mmol) 3-側氧基丁酸乙酯及1.35 g (22.5 mmol) AcOH之混合物在流動中使用Vapourtec R2C+/R4 (解列壓力設定為40 bar；SS管式反應器；溶液壓力設定為250psi BPR)於二噁烷中以0.2 mL/分鐘之流動速率在250℃下反應。該反應使用MeOH (流動速率0.25 mL/分鐘)淬滅。濃縮所得溶液並於EtOAc中研磨以提供呈灰白色固體之1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-醇。RT 0.95分鐘(方法2)。MS (M+1): 178.2。 步驟2： 在130℃下將裝有於苯甲醚(8 mL)中之1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-醇(1g, 5.64 mmol)及POCl3 (0.631 mL, 6.77 mmol)之密封容器加熱2小時。使該反應冷卻下來且在真空中移除溶劑並乾燥以提供4-氯-1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶(HG13)。RT 0.52分鐘(LC/MS方法2)。MS (M+1): 196.6。例示性化合物之合成 實例1 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)之合成 步驟 1 ： 向含有(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (0.565 g, 42.5 mmol)之壓力燒瓶添加4-溴-1,6-二甲基-1H-吡唑并[3,4-b]吡啶(HG1) (0.94 g, 2.5 mmol)、碳酸銫(1.63 g, 5.0 mmol)、Pd2 (dba)3 (0.057g, 0.062 mmol)、RuPhos (0.14 g, 0.3 mmol)及THF (25 mL)。在80℃下將該混合物加熱18小時至完成，然後冷卻至室溫。將該混合物稀釋於乙酸乙酯及水中。分層後，水層用乙酸乙酯再萃取一次。組合兩個有機層，於MgSO4 上乾燥，過濾並在真空中濃縮。殘餘物係經由急速層析術使用0至100% B/A (A=庚烷；B= 25%乙醇於乙酸乙酯中)以溶析(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯來純化：1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 6.27 (s, 1H), 4.49 (s, 2H), 4.38 - 4.25 (m, 1H), 4.11 (s, 3H), 3.94 (t, J = 5.5 Hz, 2H), 3.70 (s, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.62 (s, 3H), 2.25 (s, 3H), 1.89 - 1.75 (m, 6H), 1.58 (m, 6H), 1.42 (s, 9H)；針對C29 H72 N7 O2 (M+H+ )，MS計算值520.34，實測值520.4。步驟 2 ： 向含有(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(1.5 g, 1.45 mmol)之500 mL圓底燒瓶添加甲醇(6 mL)，然後添加於二噁烷中之4 N HCl (7.2 mL, 28.9 mmol)。在室溫下將該混合物攪拌18小時然後在真空中濃縮。殘餘物用異丙醇在70℃下分批處理以使所有固體溶解。讓該溶液自然冷卻至室溫並老化18小時。然後過濾固體並濃縮濾液且重複結晶過程。組合兩個批次並在真空下在40℃下乾燥18小時以提供呈HCl鹽之4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物-HCl)：1 H NMR (400 MHz, CD3 OD) δ 8.51 (s, 1H), 6.88 (s, 1H), 5.06 - 4.92 (m, 2H), 4.24 (s, 2H), 4.11 (s, 3H), 3.97 (s, 2H), 3.10 (t, J = 5.6 Hz, 2H), 2.69 (s, 3H), 2.38 (s, 3H), 1.88 - 1.59 (m, 12H); MS (M+H+ )，實測值420.3。步驟 3 ： 將Ambersep 900OH (17 ml, 0.8毫當量/ mL，用60 mL MeOH預清洗)添加至呈HCl鹽之4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物-HCl) (1.53 g, 2.7 mmol)於MeOH (100 mL)中之溶液。在室溫下將該混合物攪拌1小時，然後過濾，用50 mL MeOH清洗並濃縮。將粗產物添加(藉由固體裝載)至12 g矽膠管柱並用於DCM中之2至9% MeOH (含有少量氨)溶析。收集溶離份並濃縮以產生呈游離鹼之產物4-((5- (1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)：1 H NMR (400 MHz, CD3 OD) δ 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J = 5.6 Hz, 2H), 3.73 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.55 (s, 12H)；MS (M+H+ ) 420.3。實例2 4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(2號化合物)及4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(53號化合物)之合成 步驟1：將(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (110 mg, 0.294 mmol)、三氟甲磺酸1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基酯(HG7) (118 mg, 0.294 mmol)、DIPEA (0.154 mL, 0.881 mmol)及BuOH (0.05 mL)添加至反應小瓶及然後在120℃下攪拌3小時。反應混合物藉由HPLC純化以產生(4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。RT (方法2)：2.29分鐘，ESIMS m/z 626.4 (M+ + 1)。 步驟2：向(4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(110 mg, 0.176 mmol)於MeOH (1 mL)中之溶液添加鹽酸(0.879 mL, 5.27 mmol)。在25℃下將該反應攪拌16小時及然後乾燥以產生呈HCl鹽之4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(53號化合物)。RT (方法1)：1.28分鐘，ESIMS m/z 526.3 (M+ + 1)。 步驟3：向20 mL壓力管添加4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(53號化合物) (80 mg, 0.152 mmol)、半胱胺酸(36.9 mg, 0.304 mmol)及TFA (2 mL)。在75℃下將該混合物加熱2小時及然後冷卻至室溫並在真空中濃縮。殘餘物藉由HPLC純化以產生4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(2號化合物)。ESIMS m/z 406.2 (M+ + 1)；1 H NMR (400 MHz，甲醇-d4 ) δ 8.09 (s, 1H), 6.34 (s, 1H), 4.44 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 4H), 2.80 (t, J = 5.6 Hz, 2H), 2.41 (s, 3H), 2.13 (s, 3H), 1.44 (s, 12H)。實例3 4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(3號化合物)及(4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(147號化合物)之合成 步驟1：向反應小瓶添加(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (105 mg, 0.280 mmol)、4-氯-2-甲基-1,7-萘啶(HG9) (50 mg, 0.280 mmol)、DIPEA (0.147 mL, 0.840 mmol)及BuOH (0.1 mL)。在120℃下將該反應攪拌3小時，用甲醇稀釋並藉由HPLC純化。匯集溶離份，用Na2 CO3 中和及然後用乙酸乙酯萃取以產生(4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(147號化合物)。1 H NMR (400 MHz, DMSO-d6 ) δ 9.53 (s, 1H), 8.73 (d, J = 5.9 Hz, 1H), 8.34 - 7.92 (m, 2H), 7.39 (s, 1H), 4.68 (s, 2H), 4.03 (t, J = 5.2 Hz, 2H), 3.72 (s, 2H), 3.08 (s, 2H), 2.78 (s, 3H), 2.51 (s, 9H), 2.12 (s, 3H), 1.80 - 1.45 (m, 12H)。ESIMS m/z 518.0 (M+ + 1)。 步驟2：向(4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(124 mg, 0.240 mmol)於MeOH (1 mL)中之溶液添加鹽酸(1.200 mL, 7.20 mmol)。在25℃下將該反應攪拌16小時。乾燥該反應以產生呈HCl鹽之4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(3號化合物)。ESIMS m/z 417.2 (M+ + 1)；1 H NMR (400 MHz, DMSO-d6 ) δ 9.53 (s, 1H), 8.73 (d, J = 5.9 Hz, 1H), 8.16 - 8.05 (m, 4H), 7.39 (s, 1H), 4.70 (s, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.13 - 3.03 (m, 2H), 2.78 (s, 3H), 2.12 (s, 3H), 1.75 - 1.63 (m, 6H), 1.60 - 1.49 (m, 6H)。 實例4 4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(4號化合物)及(4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(146號化合物)之合成步驟1：向反應小瓶添加(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (67.0 mg, 0.179 mmol)、4-氯-2-甲基-7H-吡咯并[2,3-d]嘧啶(HG14) (30 mg, 0.179 mmol)、DIPEA (0.094 mL, 0.537 mmol)及BuOH (0.1 mL)。在120℃下將該反應攪拌3小時及然後用甲醇稀釋並藉由HPLC純化以產生(4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(146號化合物)。RT (方法2)：2.11分鐘。MS (ES+): 507.3 (M+1)+。 步驟2：向(4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(35 mg, 0.075 mmol)於MeOH (1 mL)中之溶液添加鹽酸(0.445 mL, 2.67 mmol)。在25℃下將該反應攪拌16小時及然後乾燥以產生呈HCl鹽之4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(4號化合物)。ESIMS m/z 406.2 (M+ + 1)；1 H NMR (400 MHz，甲醇-d4 ) δ 7.36 (d, J = 3.5 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H), 5.18 (s, 2H), 4.47 (t, J = 5.3 Hz, 2H), 4.17 (s, 2H), 3.16 (t, J = 5.3 Hz, 2H), 2.71 (s, 3H), 2.52 (s, 3H), 1.90 - 1.66 (m, 12H)。 實例5 4-((5-(1,6-二甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(5號化合物)之合成步驟1：向反應小瓶添加(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (62.2 mg, 0.166 mmol)、4-氯-1,6-二甲基-1H-吡咯并[2,3-b]吡啶(HG15) (30 mg, 0.166 mmol)、RuPhos (9.30 mg, 0.020 mmol)、參(二亞苄丙酮)二鈀(0) (7.60 mg, 8.30 µmol)、Cs2 CO3 (108 mg, 0.332 mmol)及THF (2 mL)。在75℃下將該反應攪拌18小時。反應完成。該反應用乙酸乙酯稀釋並濾過矽藻土以移除鹽。乾燥濾液且粗產物直接用於下一步驟中。 步驟2：向(4-((5-(1,6-二甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(30 mg, 0.046 mmol)於MeOH (1 mL)中之溶液添加鹽酸(0.231 mL, 1.388 mmol)。在25℃下將該反應攪拌16小時，然後乾燥並藉由HPLC純化以產生-((5-(1,6-二甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(5號化合物)：ESIMS m/z 419.2 (M+ + 1)；1 H NMR (400 MHz，甲醇-d4 ) δ 7.14 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.66 (s, 1H), 4.67 (s, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.79 (s, 3H), 3.69 (s, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.13 (s, 3H), 1.66 (dd, J = 10.9, 4.6 Hz, 6H), 1.56 (dd, J = 10.8, 4.7 Hz, 6H)。 實例6 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺(6號化合物)之合成向4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物，1.68 g, 4.0 mmol)於DCE (40 mL)中之溶液添加乙酸(0.229 mL, 1.0當量)及氧雜環丁烷-3-酮(2.94 g, 10當量)。在室溫下將該混合物攪拌30分鐘，然後添加三乙醯氧基硼氫化鈉(2.62 g, 3.0當量)。然後在室溫下將該混合物攪拌整夜。添加更多之氧雜環丁烷-3-酮(1.47 g, 5當量)、三乙醯氧基硼氫化鈉(1.3 g, 1.5當量)及20 mL DCE並在室溫下將該混合物攪拌額外之5小時然後用40 mL 1 N NaOH處理。將層分離且水層用DCM/MeOH (5:1 v/v, 100 mL x 3)萃取。經組合之有機層於Na2 SO4 上乾燥，過濾並濃縮以產生粗產物。將該粗產物添加至40 g金矽膠管柱並用於DCM中之0至50% (歷時25分鐘) IPA (含有0.02 M氨)溶析。收集溶離份並濃縮以產生N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺(6號化合物)：1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.60 (t, J = 6.8 Hz, 2H), 4.43 (s, 2H), 4.34 (t, J = 6.6 Hz, 2H), 4.04 (p, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 1.47 - 1.33 (m, 12H)。MS (ES+): 476.3 (M+1)+。 實例7 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺(7號化合物)之合成向4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物，2.52 g, 6.0 mmol)及2-(二甲基胺基)乙酸(0.742g, 1.2當量)於DCM (60 mL)中之混合物添加DIPEA (2.1 mL, 2.0當量)，然後添加HATU (2.74 g, 1.2當量)。在室溫下將所得混合物攪拌1小時，然後用30 mL水清洗。水層用DCM (100 mL x 3)萃取及經組合之有機層於Na2 SO4 上乾燥，過濾並濃縮以產生粗產物。將該粗產物添加至80 g金矽膠管柱並用於DCM中之0至50% (歷時30分鐘) IPA (含有0.02 M氨)溶析。收集溶離份並濃縮以產生N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺(7號化合物)：1H NMR (600 MHz，甲醇-d4) δ 8.17 (s, 1H), 6.47 (s, 1H), 4.56 (s, 2H), 4.02 (s, 3H), 3.99 (dd, J = 6.1, 5.1 Hz, 2H), 3.74 (s, 2H), 2.94 - 2.91 (m, 2H), 2.90 (s, 2H), 2.56 (s, 3H), 2.36 (s, 1H), 2.30 (s, 6H), 2.25 (s, 3H), 1.94 - 1.87 (m, 6H), 1.63 - 1.57 (m, 6H)。MS (ES+): 505.4 (M+1)+。 實例8 (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺(8號化合物)之合成向4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物) (42 mg, 0.1 mmol)、(S)-4-(第三丁氧基羰基)嗎啉-3-羧酸(25.4 mg, 0.11 mmol)及DIPEA (0.035 mL, 0.2 mmol)於1.0 mL DMF中之混合物添加HATU (45.6 mg, 0.12 mmol)，然後在室溫下攪拌30分鐘。LC-MS證實反應完成。中間物係藉由質量誘發之HPLC (10至90% ACN於H2 O中，歷時3.5分鐘)純化。濃縮經收集之溶離份並將殘餘物溶解於MeOH/1,4-二噁烷(1.5 mL, 1:2 v/v)中。添加於1,4-二噁烷中之4 M HCl (1.0 mL)並在室溫下將該混合物攪拌1小時，然後濃縮並凍乾以產生呈HCl鹽之(S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺(8號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.52 (s, 1H), 7.92 (s, 1H), 6.88 (s, 1H), 5.06 - 4.91 (m, 2H), 4.25 (s, 2H), 4.19 - 4.09 (m, 4H), 4.03 - 3.89 (m, 4H), 3.78 - 3.56 (m, 4H), 3.22 (ddd, J = 12.9, 11.2, 3.7 Hz, 1H), 3.17 - 3.05 (m, 2H), 2.70 (s, 3H), 2.41 (s, 3H), 1.93 (dd, J = 8.9, 5.0 Hz, 6H), 1.72 - 1.54 (m, 6H)。MS (ES+): 533.3 (M+1)+。 實例9 (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺(9號化合物)之合成向4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物) (42 mg, 0.1 mmol)、(R)-4-(第三丁氧基羰基)嗎啉-3-羧酸(25.4 mg, 0.11 mmol)及DIPEA (0.035 mL, 0.2 mmol)於1.0 mL DMF中之混合物添加HATU (45.6 mg, 0.12 mmol)，然後在室溫下攪拌30分鐘。LC-MS證實反應完成。中間物係藉由質量誘發之HPLC (10至90% ACN於H2 O中，歷時3.5分鐘)純化。濃縮經收集之溶離份並將殘餘物溶解於MeOH/1,4-二噁烷(1.5 mL, 1:2 v/v)中。添加於1,4-二噁烷中之4 M HCl (1.0 mL)並在室溫下將該混合物攪拌1小時，然後濃縮並凍乾以產生呈HCl鹽之(R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺(9號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.51 (s, 1H), 7.92 (s, 1H), 6.88 (s, 1H), 5.03 - 4.92 (m, 1H), 4.32 - 4.18 (m, 2H), 4.20 - 4.09 (m, 4H), 4.03 - 3.89 (m, 4H), 3.78 - 3.54 (m, 4H), 3.22 (ddd, J = 13.0, 11.2, 3.8 Hz, 1H), 3.15 - 3.05 (m, 2H), 2.69 (s, 3H), 2.39 (s, 3H), 1.98 - 1.85 (m, 6H), 1.62 (dd, J = 10.3, 5.9 Hz, 6H)。MS (ES+): 533.3 (M+1)+。 實例10 6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷(10號化合物)及4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(26號化合物)之合成步驟1：將7-氯-1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶(HG4) (263 mg, 1.335 mmol)、(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (500 mg, 1.335 mmol)及DIPEA (0.233 mL, 1.335 mmol)於2-丙醇(30 mL)中之混合物加熱至100℃，歷時1小時。處理及管柱層析術(溶析：2:1 EtOAc:己烷)後，獲得(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。LC-MS: MS (ES+): 535.4；RT:1.171分鐘(方法1)。 步驟2：使(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯經受實例4之步驟2中描述之相同條件以產生4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(26號化合物)。1 H NMR (400 MHz，甲醇-d4 ) δ 4.96 (s, 2H), 4.31 (t, J=5.6 Hz, 2H), 4.24 (s, 3H), 3.77 (s, 2H), 3.04-2.98 (m, 2H), 2.71 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H), 1.80-1.62 (m, 12H)。MS (ES+): 435.4 (M+1)+。 步驟3：將(60 mg, 0.138 mmol) 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(26號化合物)、101 mg (0.414 mmol) 1,1-雙(溴甲基)環丁烷及K2 CO3 (95 mg, 0.690 mmol)於2-丙醇(10 mL)中之混合物加熱至120℃，歷時72小時。冷卻至室溫後，蒸發2-丙醇，添加水且該混合物用EtOAc萃取。組合有機層，乾燥(Na2 SO3 )並濃縮。殘餘物藉由製備型LC-MS純化以產生6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷(10號化合物)。1 H NMR (400 MHz，甲醇-d4 ) δ 4.70 (s, 4H), 4.52 (s, 2H), 4.11 (s, 3H), 3.86 (t, J=5.7 Hz, 2H), 3.71 (s, 2H), 3.39 (s, 4H), 2.99 (t, J=5.5 Hz, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.18 (s, 3H), 1.58-1.40 (m, 12H)。MS (ES+): 517.3 (M+1)+。實例11 4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(83號化合物)之合成步驟1：將4,6-二氯-1-甲基-1H-吡唑并[3,4-d]嘧啶(HG16) (40 mg, 0.197 mmol)、(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (70 mg, 0.187 mmol)、Pd2dba3 (10 mg, 10.92 µmol)、RuPhos (10 mg, 0.021 mmol)及Cs2 CO3 (65 mg, 0.199 mmol)混合於二噁烷(5 mL)中並在120℃下攪拌6小時。處理及製備型LC-MS後，獲得(4-((5-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。 步驟2：將(4-((5-(6-氯-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(20 mg, 0.037 mmol)、(4-氟苯基)硼酸(10 mg, 0.071 mmol)、PdCl2 (dppf).CH2 Cl2 加成物(6 mg, 7.35 µmol)及K2 CO3 (20 mg, 0.145 mmol)混合於二噁烷(3 mL)中並在110℃下攪拌6小時。處理及製備型LC-MS後，獲得(4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。 步驟3：將(4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(10 mg, 0.017 mmol)及4 N HCl (0.152 mL, 4.99 mmol)混合於MeOH (1 mL)中並在50℃下攪拌5小時。處理及製備型LC-MS後，獲得4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(83號化合物)。1 H NMR (400 MHz，甲醇-d4 ) δ 8.55 (dd, J=8.7, 5.7 Hz, 2H), 8.27 (s, 1H), 7.21 (t, J=8.8 Hz, 2H), 4.97 (s, 2H), 4.38 (brs, 2H), 4.06 (s, 3H), 3.80 (s, 2H), 2.92 (t, J=5.4 Hz, 2H), 2.29 (s, 3H), 1.80-1.60 (m, 12H)。MS (ES+): 501.3 (M+1)+。 實例12 4-(4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)吡啶-2-基)苄腈(84號化合物)之合成步驟1：將2-氯-4-氟吡啶(130 mg, 0.988 mmol)、(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(TG3) (370 mg, 0.988 mmol)及DIPEA (130 mg, 1.006 mmol)混合於DMA (5 mL)中並在150℃下攪拌4小時。處理及管柱層析術(2:1 EtOAc:己烷)後，獲得(4-((5-(2-氯吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。 步驟2：將(4-((5-(2-氯吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(25 mg, 0.051 mmol)、(4-氰基苯基)硼酸(15 mg, 0.102 mmol)、PdCl2 (dppf).CH2 Cl2 加成物(5 mg, 6.12 µmol)及K2 CO3 (25 mg, 0.181 mmol)混合於二噁烷(3 mL)中並在120℃下攪拌17小時。處理及製備型LC-MS後，獲得(4-((5-(2-(4-氰基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。 步驟3：將(4-((5-(2-(4-氰基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯(20 mg, 0.036 mmol)及4 N HCl (0.220 mL, 7.24 mmol)混合於MeOH (1 mL)中並在50℃下攪拌3小時。處理及製備型LC-MS後，獲得4-(4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)吡啶-2-基)苄腈(84號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.25 (d, J=7.4 Hz, 1H), 8.08-7.97 (m, 4H), 7.56 (brs, 1H), 7.36 (m, 1H), 4.71 (s, 2H), 4.09 (brs, 2H), 3.79 (s, 2H), 2.93 (t, J=5.4 Hz, 2H), 2.25 (s, 3H), 1.82-1.60 (m, 12H)。MS (ES+): 453.3 (M+1)+。 實例13 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶(58號化合物)之合成4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物) (23 mg, 0.055 mmol)用碳酸鉀(22.73 mg, 0.164 mmol)、1,4-二溴丁烷(59.2 mg, 0.274 mmol)及乙醇(548 µL)處理。藉由微波照射將該混合物加熱至120℃，歷時30分鐘。該混合物用乙酸乙酯及1 N NaOH稀釋。萃取後，水層用乙酸乙酯反萃取兩次。組合有機層，用MgSO4 乾燥並在真空中濃縮。將殘餘物裝載於4 g矽膠管柱上使用0至50% IPA/DCM以3%氨作為改質劑以獲得5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶(化合物58)。1H NMR (400 MHz，甲醇-d4) δ 8.06 (s, 1H), 6.36 (s, 1H), 4.45 (s, 2H), 3.99 (s, 3H), 3.89 (m, 2H), 3.64 (s, 2H), 2.81 (m, 2H), 2.64 (s, 4H), 2.45 (s, 3H), 2.13 (s, 3H), 1.68 (s, 4H), 1.63 - 1.35 (m, 12H)。ESIMS (M+H+) 475.2。 實例14 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉(59號化合物)之合成4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉係使用實例13中描述之方法獲得，除使用1-溴-2-(2-溴乙氧基)乙烷(63.6 mg, 0.274 mmol)置換1,4-二溴丁烷外。1H NMR (400 MHz，甲醇-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 3.99 (d, J = 9.5 Hz, 5H), 3.73 (s, 2H), 3.68 - 3.51 (m, 4H), 2.91 (t, J = 5.4 Hz, 2H), 2.23 (s, 3H), 1.57 (m, 12H)。ESIMS (M+H+) 491.0。 實例15 1-((4-(1H-咪唑-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶(119號化合物)之合成將4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物) (55 mg, 0.131 mmol)溶於水(807 µL)中並添加1滴亞磷酸(pH: ~1)。添加於水中之多聚甲醛(4.72 mg, 0.157 mmol)及乙二醛(18.04 µL, 0.157 mmol) 40%並將所得混合物加熱至80℃。歷時10分鐘滴加溶解於水(202 µL)中之氯化銨(8.41 mg, 0.157 mmol)之溶液並將所得混合物加熱至110℃，歷時18小時，LC-MS顯示仍~50%未經轉化之起始材料。將額外之47 mg多聚甲醛、乙二醛(18 mL)及NH4 Cl (84 mg)添加至該混合物(讓它完成)。在110℃下將該混合物加熱18小時。使用Na2 CO3 水溶液將該反應混合物調整至pH 8至9，用DCM萃取兩次。濃縮有機層並裝載於4 g矽膠管柱上使用於DCM中之0至50% IPA以3% NH3 作為改質劑以提供1-((4-(1H-咪唑-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶(化合物119)。1H NMR (400 MHz，甲醇-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.01 (s, 3H), 3.91 (m, 2H), 3.73 (s, 2H), 3.68 - 3.51 (m, 4H), 2.91 (m, 2H), 2.55 (m, 4H), 2.52 (s, 3H), 2.23 (s, 3H), 1.57 (m, 12H)。ESIMS (M+H+)實測值471.6。 實例16 4-((3-甲基-5-(6-甲基-1-(甲基-d3)-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(140號化合物)之合成在0℃下向於含有3 mL DMF之20 mL圓底燒瓶中之(4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯及K2 CO3 之混合物滴加CD3I (27.7 µL CD3 I於1 mL DMF中之0.1 mL溶液)。將所得混合物緩慢升溫至室溫並攪拌整夜。然後濃縮該混合物，然後藉由ISCO (4 g矽膠管柱，0至10% MeOH於DCM中作為溶析液)純化以提供(4-((3-甲基-5-(6-甲基-1-(甲基-d3)-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯。RT = 1.13分鐘(方法1), MS (ES+): 524.3 (M+1)+。向11.5 mg (0.022 mmol) (4-((3-甲基-5-(6-甲基-1-(甲基-d3)-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯於1 mL二噁烷及0.1 mL MeOH中之溶液添加1 mL於二噁烷中之4 M HCl。在室溫下將所得混合物攪拌1小時，然後濃縮並凍乾以產生呈HCl鹽之所需產物(140號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.51 (s, 1H), 6.88 (s, 1H), 5.04 - 4.94 (m, 2H), 4.25 (s, 2H), 3.98 (s, 2H), 3.78 - 3.56 (m, 2H), 3.11 (d, J = 5.1 Hz, 2H), 2.70 (s, 3H), 2.39 (s, 3H), 1.85 - 1.66 (m, 12H)。MS (ES+): 423.3 (M+1)+。 實例17 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基雙環[2.2.2]辛-1-胺(43號化合物)之合成向於100 mL圓底燒瓶中之4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(來自實例1之1號化合物)於THF/MeOH (5 mL/1.5 mL)中之溶液添加DIPEA (0.13 mL, 97 mg, 0.75 mmol)。在室溫下將該混合物攪拌10分鐘，然後添加甲醛(0.037 mL, 37重量%於水中)。在室溫下將所得混合物攪拌30分鐘，然後添加NaBH3 CN (157 mg, 2.5 mmol)。然後在室溫下將該混合物攪拌整夜，藉由添加2.0 mL水淬滅，然後用DCM萃取。經組合之有機層然後於Na2 SO4 上乾燥，然後濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之0至8% MeOH (含有非常少量之氨)溶析。收集溶離份並濃縮，然後凍乾以產生所需產物4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基雙環[2.2.2]辛-1-胺。1H NMR (600 MHz，甲醇-d4) δ 8.07 (s, 1H), 6.39 (s, 1H), 4.47 (s, 3H), 3.86 (s, 5H), 3.63 (d, J = 2.5 Hz, 2H), 2.78 (t, J = 5.6 Hz, 2H), 2.58 (s, 6H), 2.41 (s, 3H), 2.07 (s, 3H), 1.71 - 1.65 (m, 6H), 1.55 - 1.49 (m, 6H)。MS (ES+): 448.4 (M+1)+。 實例18 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)甲磺醯胺(48號化合物)之合成在0℃下向57 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)及39 mg (0.052 mL, 0.3 mmol) DIPEA於2 mL DCM中之混合物添加14.9 mg (10.1 µL, 0.13 mmol)甲磺醯氯。將所得混合物緩慢升溫至室溫並攪拌2小時。將粗產物添加(藉由固體裝載)至4 g矽膠管柱並用於DCM中之0至7% MeOH (含有非常少量之氨)溶析，且藉由質量誘發之HPLC進一步純化。收集溶離份，添加1.0 mL 1 N HCl水溶液，然後濃縮並凍乾以產生呈HCl鹽之N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)甲磺醯胺(48號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.53 (s, 1H), 6.89 (s, 1H), 5.06 - 4.94 (m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98 (s, 2H), 3.18 - 3.06 (m, 2H), 2.94 (s, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 1.96 - 1.85 (m, 6H), 1.67 - 1.57 (m, 6H)。MS (ES+): 498.2 (M+1)+。 實例19 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺(50號化合物)及(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)(甲基)胺甲酸第三丁酯(49號化合物)之合成步驟1：4-溴-1,6-二甲基-1H-吡唑并[3,4-b]吡啶(HG1) (67 mg, 0.295 mmol)、(4-((3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁基甲酯(TG10) (115 mg, 0.295 mmol)、Pd2 dba3 (6.8 mg, 0.074 mmol)、RuPhos (17 mg, 0.035 mmol)及Cs2 CO3 (192 mg, 0.590 mmol)於THF中之混合物用氬沖洗，然後加熱至75℃，歷時15小時。將反應混合物冷卻至室溫然後稀釋於乙酸乙酯及水中。將層分離且水層用乙酸乙酯萃取。經組合之有機層於Na2 SO4 上乾燥，在真空中過濾並濃縮。將粗產物添加至12 g矽膠管柱並用於DCM中之0至5%甲醇溶析。收集溶離份並濃縮以產生(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)(甲基)胺甲酸第三丁酯(49號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 5H), 3.72 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.80 (s, 3H), 2.55 (s, 3H), 2.23 (s, 3H), 2.04 - 1.91 (m, 6H), 1.60 - 1.52 (m, 6H), 1.43 (s, 9H)。MS (ES+): 534.4 (M+1)+。 步驟2：向90 mg (0.169 mmol) (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)(甲基)胺甲酸第三丁酯(49號化合物)於二噁烷/MeOH (1 mL/1 mL)中之溶液添加HCl (2 mL於二噁烷中之4 M溶液)。在室溫下將所得混合物攪拌2小時。LC-MS顯示反應完成。濃縮反應混合物並將殘餘物溶解於2.0 mL MeOH中然後添加Ambersep 900 OH (0.8毫當量/ mL，5.0當量，用5.0 mL MeOH預先清洗)並在室溫下將該混合物攪拌1小時。過濾並用10 mL MeOH清洗然後濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之2至9% MeOH (含有少量之氨)溶析。收集溶離份並濃縮然後凍乾以產生4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺(50號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.36 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.88 (t, J = 5.8 Hz, 2H), 3.64 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H)。MS (ES+): 434.3 (M+1)+。 實例20 (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸1-甲基環丙酯(51號化合物)之合成向57 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)於1 mL DMA中之懸浮液添加DIPEA (52 mg, 0.4 mmol)，然後添加(4-硝苯基)碳酸1-甲基環丙酯(24 mg, 0.1 mmol)。在微波照射下在150℃下將所得混合物加熱2小時。該反應混合物用水稀釋並用EtOAc萃取。經組合之有機層用鹽水清洗，於上Na2 SO4 乾燥並濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之0至8% MeOH溶析。收集溶離份並濃縮然後凍乾以產生(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸1-甲基環丙酯(51號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.74 - 1.63 (m, 6H), 1.50 - 1.40 (m, 6H), 1.35 (s, 3H), 0.71 - 0.61 (m, 2H), 0.48 - 0.41 (m, 2H)。MS (ES+): 518.3 (M+1)+。 實例21 N-(2,2-二氟乙基)-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(61號化合物)之合成向29.4 mg (0.07 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)及18.1 mg (0.024 mL, 0.14 mmol) DIPEA於1 mL THF中之混合物添加三氟甲磺酸2,2-二氟乙酯(16.5 mg (10.3 µL, 0.077 mmol)。在85℃下將所得混合物攪拌2小時。LC-MS顯示所需產物及反應完成。將粗產物直接添加至4 g矽膠管柱並用於DCM中之2至9% MeOH (含有少量之氨)溶析。收集溶離份並濃縮然後凍乾以產生N-(2,2-二氟乙基)-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(61號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.36 (s, 1H), 5.79 (tt, J = 55.9, 4.1 Hz, 1H), 4.44 (s, 2H), 3.89 (m, 5H), 3.64 (s, 2H), 2.94 - 2.75 (m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H)。MS (ES+): 484.2 (M+1)+。 實例22 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)雙環[2.2.2]辛-1-胺(69號化合物)及4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-甲氧基乙基)雙環[2.2.2]辛-1-胺(70號化合物)之合成在微波照射下在120℃下將21 mg (0.05 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)、43 mg (0.031 mL, 0.250 mmol) 1-溴-2-乙氧基乙烷及21 mg (0.150 mmol)碳酸鉀於EtOH (1 mL)中之混合物加熱30分鐘。LC-MS顯示所需產物1但反應未完成。將溶劑變為IPA並在油浴中在110℃下加熱整夜。LC-MS顯示兩種產物。將粗產物添加至12 g矽膠管柱並用於DCM中之0至30% IPA (含有1%氨)溶析。收集溶離份並濃縮然後凍乾以產生4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-乙氧基乙基)雙環[2.2.2]辛-1-胺(69號化合物)及4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-乙氧基乙基)雙環[2.2.2]辛-1-胺(70號化合物)。69號化合物：1H NMR (400 MHz，甲醇-d4) δ 8.16 (s, 1H), 8.05 (d, J = 8.2 Hz, 0H), 8.04 (s, 0H), 7.54 (d, J = 8.1 Hz, 0H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H), 3.73 (s, 2H), 3.35 (s, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.56 (s, 12H)。MS (ES+): 505.4 (M+1)+。 70號化合物：1H NMR (400 MHz，甲醇-d4) δ 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J = 5.5 Hz, 2H), 3.69 (s, 2H), 3.31 (d, J = 1.1 Hz, 6H), 2.90 (t, J = 5.6 Hz, 2H), 2.75 - 2.65 (m, 4H), 2.55 (s, 3H), 2.23 (s, 3H), 1.64 - 1.47 (m, 12H)。MS (ES+): 536.4 (M+1)+。 實例23 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-N-甲基雙環[2.2.2]辛-1-胺(73號化合物)之合成在微波照射下在150℃下將12 mg (0.028 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺(50號化合物)、19 mg (0.013 mL, 0.138 mmol) 1-溴-2-甲氧基乙烷及11.5 mg (0.083 mmol) K2 CO3 於IPA中之混合物加熱1小時。將粗產物直接添加至4 g矽膠管柱並用於DCM中之0至30% IPA (含有1%氨)溶析。收集溶離份並濃縮然後凍乾以產生4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-N-甲基雙環[2.2.2]辛-1-胺(73號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H), 3.72 (s, 2H), 3.43 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.63 (s, 2H), 2.55 (s, 3H), 2.23 (s, 6H), 1.67 - 1.49 (m, 12H)。MS (ES+): 492.4 (M+1)+。 實例24 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-N,N-二甲基乙醯胺(76號化合物)之合成。在室溫下將42.0 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)、18.3 mg (0.11 mmol) 2-溴-N,N-二甲基乙醯胺及65.2 mg (0.2 mmol)碳酸銫於1 mL DMF中之混合物攪拌整夜。將粗產物添加至4 g矽膠管柱並用於DCM中之0至30% IPA (含有1%氨)溶析。收集溶離份並濃縮然後凍乾以提供2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-N,N-二甲基乙醯胺(76號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.17 (d, J = 1.8 Hz, 1H), 6.47 (s, 1H), 4.56 (s, 2H), 4.02 (s, 3H), 4.00 (t, J = 5.7 Hz, 2H), 3.76 (m, 2H), 3.56 (m, 2H), 3.03 - 2.95 (m, 6H), 2.92 (t, J = 5.6 Hz, 2H), 2.56 (s, 3H), 2.25 (s, 3H), 1.73 - 1.56 (m, 12H)。MS (ES+): 505.4 (M+1)+。 實例25 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-N-甲基氧雜環丁烷-3-胺(77號化合物)之合成向2.1 mg (4.4 µmol N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺(6號化合物)於THF (1 mL)中之溶液添加乙酸(1.33 mL (1.26 µL, 0.022 mmol)及10.9 mg (0.134 mmol)甲醛。在室溫下將該混合物攪拌1小時，然後添加氰基硼氫化鈉。然後在室溫下將所得混合物攪拌整夜。該反應藉由添加0.1 mL水淬滅然後濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之0至50% IPA (含有1%氨)溶析。收集溶離份並濃縮然後凍乾以提供N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-N-甲基氧雜環丁烷-3-胺(77號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.58 (t, J = 6.9 Hz, 2H), 4.47 (t, J = 7.0 Hz, 2H), 4.44 (s, 2H), 4.25 (q, J = 7.3 Hz, 1H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.45 (s, 12H)。MS (ES+): 490.4 (M+1)+。 實例26 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基-2-甲基丙基)雙環[2.2.2]辛-1-胺(101號化合物)之合成步驟1：向14.2 mg (0.12 mmol) 2-甲氧基-2-甲基丙酸於DMF (2 mL)中之溶液添加HATU (45.6 mg, 0.12 mmol)及DIPEA (0.035 mL, 25.8 mg, 0.2 mmol)。在室溫下將該混合物攪拌5分鐘，然後添加42.0 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)。然後在室溫下將所得混合物攪拌1小時。LC-MS顯示反應完成。將該混合物分配至EtOAc與水之間。將層分離且水層用EtOAc萃取。經組合之有機層在Na2 SO4 上乾燥，然後濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之0至50% IPA (含有1%氨)溶析。收集溶離份並濃縮然後凍乾以提供N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲氧基-2-甲基丙醯胺。1H NMR (400 MHz，甲醇-d4) δ 8.19 (s, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 4.58 (s, 2H), 3.96 (t, J = 5.4 Hz, 2H), 3.94 (s, 3H), 3.64 (s, 2H), 3.12 (s,3H), 2.84 (t, J = 5.6 Hz, 2H), 2.49 (s, 3H), 2.14 (s, 3H), 1.83 - 1.73 (m, 6H), 1.53 - 1.43 (m, 6H), 1.17 (s, 6H)。MS (ES+): 520.3 (M+1)+。 步驟2：在0℃下向17 mg (0.033 mmol) N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲氧基-2-甲基丙醯胺於THF (1 mL)中之經攪拌之溶液添加6.5 mg (0.164 mmol) LiAlH4 。然後將所得混合物緩慢升溫至室溫並攪拌整夜。在0℃下冷卻後，該反應用IPA然後用水淬滅並濃縮。將粗產物添加(藉由固體裝載)至4 g矽膠管柱並用於DCM中之0至30% IPA (含有1%氨)溶析。收集溶離份並濃縮然後藉由質量誘發之HPLC進一步純化以提供4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基-2-甲基丙基)雙環[2.2.2]辛-1-胺(101號化合物)，其使用Ambersep 900 OH (強鹼性陰離子交換劑)中和。1H NMR (600 MHz，甲醇-d4) δ 8.05 (d, J = 1.1 Hz, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.90 - 3.85 (m, 2H), 3.64 (d, J = 6.3 Hz, 2H), 3.07 (s, 2H), 2.83 - 2.77 (m, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.57 - 1.46 (m, 12H), 1.07 (s, 6H)。MS (ES+): 506.4 (M+1)+。 實例27 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-1-甲基哌嗪-2-酮(104號化合物)之合成步驟1：向4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物) (121 mg, 0.246 mmol)於CPME (12.3 mL)中之溶液添加甲基(2-側氧基乙基)胺甲酸第三丁酯(63.8 mg, 0.369 mmol)。在25℃下將該混合物攪拌30分鐘，然後添加三乙醯氧基硼氫化鈉(156 mg, 0.737 mmol)。然後在25℃下將該混合物攪拌3小時。濃縮該混合物並使用於DCM中之0至40% IPA以2% NH3 作為改質劑於4 g矽膠管柱上純化來溶析88.6 mg (0.154 mmol) (2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)乙基)(甲基)胺甲酸第三丁酯。RT(方法1)：1.26分鐘，MS (ES+): 577.4 (M+1)+。 步驟2：在微波照射下在150℃下將40 mg (0.069 mmol) (2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)乙基)(甲基)胺甲酸第三丁酯、35.5 mg (0.024 mL, 0.208 mmol) 2-溴乙酸乙酯及10.5 mg (0.076 mmol)碳酸鉀於EtOH (1 mL)中之混合物加熱1小時。LC-MS顯示反應完成。使該反應冷卻下來至室溫，添加1 N NaOH水溶液並在室溫下將該混合物攪拌3小時。然後該反應混合物用 2 mL水稀釋且有機溶劑在旋轉蒸發儀上移除並用Et2 O (3 mL)清洗。然後水層用1 N HCl水溶液小心酸化至~pH 3。用EtOAc萃取，然後用DCM/MeOH萃取，但基於LC-MS大部分產物仍留在水相中。濃縮水相及有機相兩者，然後藉由質量誘發之HPLC純化以提供2-((2-((第三丁氧基羰基)(甲基)胺基)乙基)(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)乙酸。RT (方法2)：1.72分鐘，MS (ES+): 634.8 (M+1)+。 步驟3：向27.0 mg (0.043 mmol) 2-((2-((第三丁氧基羰基)(甲基)胺基)乙基)(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)乙酸於1 mL 1,4-二噁烷中之混合物添加0.3 mL MeOH以獲得澄清溶液。滴加於二噁烷中之4 M HCl並在室溫下將所得混合物攪拌1小時。LC-MS顯示反應完成。濃縮該混合物並將殘餘物溶解於2.0 mL DMF及DIPEA (38 µL, 5當量)中然後在0℃下滴加至HATU (21 mg, 1.3當量)於3.0 mL DMF中之溶液內。在0℃下將所得混合物攪拌30分鐘。LC-MS顯示反應完成。粗產物藉由質量誘發之HPLC (10至20% ACN於H2 O中，歷時3.5分鐘)純化然後使用鹼性樹脂中和以提供4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-1-甲基哌嗪-2-酮(104號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H), 3.62 (s, 2H), 3.17 (dd, J = 6.3, 4.5 Hz, 2H), 3.08 (s, 2H), 2.80 (m, 5H), 2.66 (dd, J = 6.3, 4.5 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.48 (tq, J = 9.4, 6.4, 4.7 Hz, 12H)。MS (ES+): 517.3 (M+1)+。 實例28 1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基哌嗪-2-酮(108號化合物)之合成步驟1：在0℃下向80 mg (0.139 mmol) (2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)乙基)(甲基)胺甲酸第三丁酯(實例27，步驟1)及36 mg (0.048 µL, 0.277 mmol) DIPEA於1.0 mL DCM中之混合物滴加2-溴乙醯溴(0.062 mL , 0.694 mmol)於DCM (1.0 mL)中之溶液內。將所得混合物緩慢升溫至室溫並攪拌1小時。然後該反應藉由添加0.1 mL水淬滅並濃縮。將粗產物添加至4 g矽膠管柱並用於DCM中之0至30% IPA (含有0.02 M氨)溶析。收集溶離份並濃縮以提供(2-(2-溴-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺基)乙基)(甲基)胺甲酸第三丁酯。RT (方法1)：1.45分鐘。MS (ES+): 701.2, 700.3 (M+1)+。 步驟2：向40.0 mg (0.057 mmol) (2-(2-溴-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺基)乙基)(甲基)胺甲酸第三丁酯於1 mL 1,4-二噁烷中之混合物添加0.5 mL MeOH以獲得澄清溶液。滴加於二噁烷中之4 M HCl (0.5 mL, 2.0 mmol)並在室溫下將所得混合物攪拌30分鐘。LC-MS顯示反應完成。濃縮該混合物並向殘餘物添加5.0 mL DMF及碳酸銫。在室溫下將所得混合物攪拌1小時並濃縮。粗產物藉由質量誘發之HPLC (10至20% ACN於H2 O中，歷時3.5分鐘)純化然後添加1 N HCl水溶液並凍乾以提供呈HCl鹽之1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基哌嗪-2-酮(108號化合物)。1H NMR (400 MHz，甲醇-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H), 3.62 (s, 2H), 2.80 (t, J = 5.5 Hz, 2H), 2.45 (m, 5H), 2.17 (dd, J = 7.9, 6.9 Hz, 2H), 2.14 (s, 6H), 2.13 (s, 3H), 1.80 - 1.73 (m, 6H), 1.50 - 1.43 (m, 6H)。MS (ES+): 519.3 (M+1)+。 實例29 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-氟氮雜環丁烷-1-基)乙醯胺(133號化合物)之合成步驟1：向16.7 mg (0.120 mmol) 2-溴乙酸及42.0 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)於DCM (1 mL)中之混合物添加HATU (45.6 mg, 0.12 mmol)及DIPEA (25.8 mg, 0.035 mL, 0.2 mmol)。在室溫下將所得混合物攪拌1小時。LC-MS證實反應完成並濃縮該混合物。將粗產物添加至4 g矽膠管柱並用於DCM中之0至50% IPA (含有0.02 M氨)溶析。收集溶離份並濃縮以提供2-溴-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺。RT (方法1)：1.26分鐘。MS (ES+): 540.2及542.1 (M+1)+。 步驟2：在120℃下在微波照射下將27 mg (0.05 mmol) 2-溴-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺、7.3 mg (0.065 mmol) 3-氟氮雜環丁烷及20.7 mg (0.15 mmol)碳酸鉀於DMA (1 mL)中之混合物加熱40分鐘。濃縮後，粗產物藉由質量誘發之HPLC (10至30% ACN於H2 O中，歷時3.5分鐘)純化然後添加1 N HCl水溶液並凍乾以提供呈HCl鹽之N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-氟氮雜環丁烷-1-基)乙醯胺(133號化合物)。RT (方法1)：1.04分鐘。MS (ES+): 535.3 (M+1)+。 實例30 N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-羥基乙醯胺(135號化合物)及N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-羥基氮雜環丁烷-1-基)乙醯胺(136號化合物)之合成。步驟1：向10.1 mg (0.11 mmol) 2-側氧基乙酸及42 mg (0.1 mmol) 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺(1號化合物)於DCM中之混合物添加HATU (41.8 mg, 0.11 mmol)及DIPEA (25.8 mg, 0.035 mL, 0.2 mmol)。然後在室溫下將所得混合物攪拌1小時然後裝載於4 g矽膠管柱上並用於DCM中之0至50% IPA (含有0.02 M氨)溶析。收集溶離份並濃縮。將殘餘物溶解於2 mL DCE中，添加氮雜環丁烷-3-醇(HCl鹽)並在室溫下將該混合物攪拌30分鐘，然後添加三乙醯氧基硼氫化鈉。然後在室溫下將該混合物攪拌整夜。LC- MS顯示一些所需產物1但主要副產物2。粗產物藉由質量誘發之HPLC (10至30% ACN於H2 O中，歷時3.5分鐘)純化然後添加1 N HCl水溶液並凍乾以產生N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-羥基氮雜環丁烷-1-基)乙醯胺(136號化合物) [RT (方法1)：1.05分鐘。MS (ES+): 478.3 (M+1)+]及N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-羥基乙醯胺(135號化合物) [RT (方法1)：0.98分鐘。MS (ES+): 533.3 (M+1)+]，兩者皆為HCl鹽。表 6 ： 額外之例示性化合物 投與及醫藥組合物 就本發明之化合物之治療用途而言，此等化合物係以治療有效量單獨或作為醫藥組合物之一部分投與。因此，本發明提供包含本發明之化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受之載劑、稀釋劑或賦形劑之醫藥組合物。出於本發明之目的，除非另有指定，否則溶劑合物及水合物一般視為組合物。較佳地，醫藥上可接受之載劑係無菌的。 本發明之醫藥組合物針對約50至70 kg之個體可以約1至1000 mg活性成分之單位劑量。化合物、醫藥組合物或其組合之治療有效劑量取決於該個體之物種、體重、年齡及治療中之個別病症、失調症或疾病或其嚴重性。具備一般技能之醫師、臨床醫生或獸醫可易於確定預防、治療或抑制失調症或疾病之進展所需之活性成分中之各者之有效量。 上文引用之劑量性質可於活體外及活體內測試中有利地使用哺乳動物(例如，小鼠、大鼠、狗、猴)或其經分離之器官、組織及製劑進行證實。本發明之化合物可以溶液之形式(例如，水溶液)活體外施用，及腸內、非經腸、有利地靜脈內，例如，作為懸浮液或於水溶液中活體內施用。活體外劑量可在約10-3 莫耳與10-9 莫耳濃度之間。活體內治療有效量可取決於投與途徑而在約0.1至500 mg/kg之間的範圍內變化。根據本發明之化合物之活性可藉由下列活體外及活體內方法進行評估。 本發明之醫藥組合物可使用包括混合本發明之化合物或其醫藥上可接受之鹽與一或多種醫藥上可接受之載劑、稀釋劑或賦形劑之方法加以製備。以實例說明之，本發明之醫藥組合物係藉由混合、造粒及/或包衣方法使用本發明之化合物以游離形式或以醫藥上可接受之鹽形式結合至少一種醫藥上可接受之載劑、稀釋劑或賦形劑進行製造。 本發明進一步提供包含作為活性成分之本發明之化合物之無水醫藥組合物及劑型，因為水可促進某些化合物之降解。 本發明之無水醫藥組合物及劑型可使用無水或低含水量成分及低水分或低濕度條件進行製備。無水醫藥組合物可經製備及儲存使得保持其無水性質。因此，無水組合物係使用已知材料包裝以防止曝露於水使得其等可包括於合適之規定套組中。合適之包裝之實例包括(但不限於)經氣密密封之箔、塑膠、單位劑量容器(例如，小瓶)、泡罩包裝及條形包裝。 本發明進一步提供包含減小作為活性成分之本發明之化合物分解之速率之一或多種藥劑之醫藥組合物及劑型。此等藥劑(本文中稱為「穩定劑」)包括(但不限於)抗氧化劑(諸如抗壞血酸)、pH緩衝劑或鹽緩衝劑等。 醫藥組合物可針對特定之投與途徑加以調配，諸如經口投與、直腸投與、透皮投與、非經腸、靜脈投與、肌內投與、肺部投與、吸入投與、鼻內投與、眼部投與及局部投與。經口投與劑型 本發明之醫藥組合物可作為離散劑型經口投與，其中此等劑型包括(但不限於)膠囊、明膠膠囊、膠囊型錠劑、錠劑、咀嚼錠、***錠、可分散粉末、顆粒、糖漿、調味糖漿、於水性或非水性液體中之溶液或懸浮液、可食用泡沫或攪打泡沫及水包油液乳膠或油包水液乳膠。 因此，就經口投與而言，包含有效量之本發明之化合物之本發明之醫藥組合物可以固體形式(包括(但不限於)膠囊、明膠膠囊、硬質或軟質膠囊、錠劑、咀嚼錠、***錠、膠囊型錠劑、丸劑、顆粒或可分散粉末)或以液體形式(包括(但不限於)溶液、水性或油性懸浮液、糖漿、酏劑、泡沫、攪打泡沫或乳劑)製成。該等醫藥組合物可經受習知醫藥操作(諸如滅菌)及/或可含有習知惰性稀釋劑、潤滑劑或緩衝劑及佐劑(諸如防腐劑、穩定劑、潤濕劑、乳化劑及緩衝劑等)。 旨在用於經口用途之組合物係根據此項技術中已知用於製造醫藥組合物之任何方法製備且此等組合物可含有選自由甜味劑、調味劑、著色劑及保藏劑組成之群之一或多種藥劑，以提供醫藥上高雅且可口之製劑。 通常，醫藥組合物係包含活性成分及以下中之一或多者之錠劑或明膠膠囊： a)稀釋劑，例如，乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纖維素及/或甘胺酸； b)潤滑劑，例如，二氧化矽、滑石、硬酯酸、其鎂鹽或鈣鹽及/或聚乙二醇；就錠劑而言亦包含 c)黏合劑，例如，矽酸鋁鎂、澱粉糊、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯啶酮；視需要 d)崩散劑，例如，澱粉、瓊脂、海藻酸或其鈉鹽或泡騰混合物；及 e)吸附劑、著色劑、調味劑及甜味劑。 錠劑可含有與適用於製造錠劑之非毒性醫藥上可接受之賦形劑混合之活性成分。此等賦形劑係(例如)惰性稀釋劑，諸如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑及崩解劑，例如，玉米澱粉或海藻酸；結合劑，例如，澱粉、明膠或***膠；及潤滑劑，例如，硬脂酸鎂、硬酯酸或滑石。錠劑可根據此項技術中已知的方法添加薄膜包衣或腸溶包衣。該等錠劑係不添加包衣或藉由已知技術添加包衣以延遲在胃腸道中之分解及吸收且藉此提供長期持續作用。例如，可採用時間延遲材料，諸如甘油單硬脂酸酯或甘油二硬脂酸酯。用於經口用途之調配物可呈現為硬質明膠膠囊，其中活性成分係與惰性固體稀釋劑(例如，碳酸鈣、磷酸鈣或高嶺土)混合，或呈現為軟質明膠膠囊，其中活性成分係與水或油介質(例如，花生油、液體石蠟或橄欖油)混合。非經腸劑型 在某些實施例中，本發明之醫藥組合物係藉由各種途徑非經腸投與，包括(但不限於)皮下、靜脈內(包括推注)、肌內及動脈內。 某些可注射組合物係水性等滲溶液或懸浮液，且栓劑係有利地製備自脂肪乳劑或懸浮液。該等組合物可經滅菌及/或含有佐劑，諸如防腐劑、穩定劑、潤濕劑或乳化劑、溶液促進劑、用於調節滲透壓之鹽及/或緩衝劑。另外，其等亦可含有其他有治療價值之物質。該等組合物係分別根據習知混合、造粒或包衣方法加以製備，且含有約0.1至75%或含有約1至50%之活性成分。局部劑型 在某些實施例中，本發明之醫藥組合物係藉由呈洗劑、凝膠、軟膏劑、溶液、乳液、懸浮液或霜劑之形式之含有本發明之化合物之醫藥組合物之局部施用投與。 適用於局部施用(例如，施用至皮膚及眼睛)之組合物包括水溶液、懸浮液、軟膏劑、霜劑、凝膠或可噴霧調配物，例如，用於藉由氣溶膠或類似物遞送。此等局部遞送系統將特定言之適用於真皮施用，例如，用於治療皮膚癌，例如，用於防曬霜、洗劑、噴霧及類似物中之預防用途。其等因此尤其適用於局部中之用途，包括此項技術中熟知的化妝品、調配物。此等可含有增溶劑、穩定劑、張力增強劑、緩衝劑及防腐劑。 如本文使用，局部施用亦可關於吸入或鼻內施用。其等可在使用或不使用合適之推進劑之情況下自乾燥粉末吸入器以乾燥粉末之形式(單獨、作為混合物，例如與乳糖之乾燥摻混物，或經混合之組分顆粒，例如與磷脂質混合之組分顆粒)或自加壓容器、泵、噴霧、霧化器或噴霧器以氣溶膠噴霧形式便利地遞送。直腸投與 在某些實施例中，本發明之醫藥組合物係以栓劑、灌腸劑、軟膏劑、乳膏直腸泡沫或直腸凝膠之形式進行直腸投與。在某些實施例中，此等栓劑係製備自脂肪乳液或懸浮液、可可脂或其他甘油酯。儲積投與 (Depot Administration) 在某些實施例中，本發明之醫藥組合物係調配成儲積製劑。此等調配物係藉由移植(例如，皮下或肌內)或藉由肌內注射進行投與。在某些實施例中，此等調配物包括聚合或疏水材料(例如，作為於可接受之油中之乳液)或離子交換樹脂，或作為微溶衍生物，例如，作為微溶鹽。組合治療 本發明之化合物及本文提供之醫藥組合物係單獨或與一或多種額外之治療劑組合投與。 本發明之組合針對約50至70 kg之個體可係以約1至1000 mg活性成分之單位劑量。該等組合之治療有效劑量係取決於個體之物種、體重、年齡及個別病症、治療中之失調症或疾病或其嚴重性。具備一般技能之醫師、臨床醫生或獸醫可容易地確定預防、治療或抑制失調症或疾病之進展所需之該等活性成分中之各者之有效量。 上文引用之劑量性質可於活體外及活體內測試中有利地使用哺乳動物(例如，小鼠、大鼠、狗、猴)或其經分離之器官、組織及製劑進行證實。本發明之化合物可以溶液之形式(例如，水溶液)活體外施用，及腸內、非經腸、有利地靜脈內，例如，作為懸浮液或於水溶液中活體內施用。活體外劑量可在約10-3 莫耳與10-9 莫耳濃度之間。活體內治療有效量可取決於投與途徑而在約0.1至500 mg/kg之間的範圍內變化。根據本發明之化合物之活性可藉由下列活體外及活體內方法進行評估。 本發明之化合物可與一或多種其他治療劑同時或之前或之後投與。本發明之化合物可藉由相同或不同之投與途徑分開投與或與其他藥劑呈現於相同醫藥組合物中一起投與。治療劑係(例如)化學化合物、肽、抗體、抗體片段或核酸，其係治療活性或當與本發明之化合物組合向病患投與時增強治療活性。 本發明提供包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及其他治療劑之醫藥組合物。視需要，如上文描述，該醫藥組合物可包含醫藥上可接受之載劑。 本發明提供包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及至少一種其他治療劑之產品作為組合製劑用於在治療中同時、分開或順序使用。在一項實施例中，該治療係對由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性介導之自體免疫疾病或病症之治療。作為組合製劑提供之產品包括包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及一起在相同醫藥組合物中之其他治療劑，或式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及以獨立形式(例如，以套組之形式)之其他治療劑之組合物。 在一實施例中，本發明提供包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及至少一種其他治療劑之產品作為組合製劑用於在治療中同時、分開或順序使用。在一項實施例中，該治療係對由TLR7、TLR7及TLR8或TLR7、TLR8及TLR9活性介導之自體免疫疾病或病症之治療。作為組合製劑提供之產品包括包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及一起在相同醫藥組合物中之其他治療劑或式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及以獨立形式(例如，以套組之形式)之其他治療劑之組合物。 本發明提供包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及至少一種其他治療劑之產品作為組合製劑用於在治療中同時、分開或順序使用。在一項實施例中，該治療係對由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性介導之自體免疫疾病或病症之治療。作為組合製劑提供之產品包括包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及一起在相同醫藥組合物中之其他治療劑或式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物及以獨立形式(例如，以套組之形式)之其他治療劑之組合物。 在一項實施例中，本發明提供包含兩種或多種不同醫藥組合物之套組，該等不同醫藥組合物中之至少一者含有式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物。在一項實施例中，該套組包含用於分別保留該等組合物之構件，諸如容器、經分開之瓶子或經分開之箔包。此套組之實例係泡罩包裝，如通常用於錠劑、膠囊及類似物之包裝。 本發明之套組可用於投與不同劑型(例如，經口及非經腸)，用於以不同劑量間隔投與各別組合物或用於相對於彼此滴定各別組合物。為有助於依從性，本發明之套組通常包含用於投與之用法說明書。 在本發明之組合治療中，本發明之化合物及其他治療劑可由相同或不同之製造商製造及/或調配。此外，本發明之化合物及其他治療劑可一起用於組合治療中：(i)在向醫師釋放組合產品之前(例如，在包含本發明之化合物及其他治療劑之套組之情況下)；(ii)在投與前即刻由醫師自己(或在醫師之指導下)；(iii)由病患自身，例如，在本發明之化合物及其他治療劑之順序投與期間。 在本文描述之組合治療之某些實施例中，本發明之化合物及額外之製劑額外地發揮作用。在本文描述之組合治療之某些實施例中，本發明之化合物及額外之治療劑協同發揮作用。 與本發明之化合物組合使用之額外之治療劑包括(但不限於)抗炎劑、免疫調節劑、免疫抑制劑、細胞介素、非類固醇抗炎藥物(NSAID)、抗瘧化合物、抗風濕化合物、B細胞活化因子(BAFF)之抑制劑、B淋巴細胞刺激劑(BLyS)之抑制劑及類固醇激素。 與本發明之化合物組合使用之非類固醇抗炎藥物(NSAID)包括(但不限於)水楊酸、乙醯水楊酸、水楊酸甲酯、二氟尼柳(diflunisal)、水楊酸鹽、奧沙拉嗪(olsalazine)、柳氮磺胺吡啶(sulfasalazine)、對乙醯胺基酚(acetaminophen)、吲哚美辛(indomethacin)、舒林酸(sulindac)、依託度酸(etodolac)、甲氧芬那酸(mefenamic acid)、甲氯芬那酸鈉(meclofenamate sodium)、托美丁(tolmetin)、酮咯酸(ketorolac)、雙氯芬酸(dichlofenac)、布洛芬(ibuprofen)、萘普生(naproxen)、萘普生鈉(naproxen sodium)、非諾洛芬(fenoprofen)、酮洛芬(ketoprofen)、氟洛芬(flurbinprofen)、奧沙普秦oxaprozin)、吡羅昔康(piroxicam)、美洛昔康(meloxicam)、安吡昔康(ampiroxicam)、屈惡昔康(droxicam)、吡羅昔康(pivoxicam)、替諾昔康(tenoxicam)、萘丁美酮(nabumetome)、保泰松(phenylbutazone)、羥基保泰松(oxyphenbutazone)、安替比林(antipyrine)、氨基比林(aminopyrine)、阿帕酮(apazone)及尼美舒利(nimesulide)。 與本發明之化合物組合使用之抗風濕化合物包括(但不限於)胺甲喋呤。 與本發明之化合物組合使用之抗瘧化合物包括(但不限於)氯喹及羥基氯喹。 與本發明之化合物組合使用之B細胞活化因子(BAFF)之抑制劑亦稱為B淋巴細胞刺激劑(BLyS)之抑制劑，包括(但不限於)貝利木單抗(Benlysta®)、Blisibimod及BR3-Fc。 與本發明之化合物組合使用之免疫抑制劑包括(但不限於)黴酚酸嗎啉乙酯(MMF)、麥考酚酸、環磷醯胺、咪唑硫嘌呤及拉喹莫德(Laquinimod) (5-氯-N-乙基-4-羥基-1-甲基-2-側氧基-N-苯基-1,2-二氫喹啉-3-甲醯胺)。 與本發明之化合物組合使用之類固醇激素包括(但不限於)脫氫表雄甾酮(DHEA)。 本發明之醫藥組合物及組合之某些態樣係提供於額外之枚舉型實施例之下列列表中。將認知各實施例中規定之特徵可與其他規定特徵組合以提供本發明之其他實施例。 實施例93：一種醫藥組合物，其包含式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例94：一種醫藥組合物，其包含式(I)或式(Ia至Ip)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例95：一種醫藥組合物，其包含式(II)或式(IIa至IIk)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例96：一種醫藥組合物，其包含式(A)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例97：一種醫藥組合物，其包含治療有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例98：一種醫藥組合物，其包含治療有效量之式(I)或式(Ia至Ip)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例99：一種醫藥組合物，其包含治療有效量之式(II)或式(IIa至IIk)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例100：一種醫藥組合物，其包含治療有效量之式(A)化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。 實施例101：本發明之醫藥組合物進一步包含一或多種獨立地選自抗炎劑、免疫調節劑、免疫抑制劑、細胞介素、非類固醇抗炎藥物(NSAID)、抗瘧化合物、抗風濕化合物、B細胞活化因子(BAFF)之抑制劑、B淋巴細胞刺激劑(BLyS)之抑制劑及類固醇激素之額外之治療劑。 實施例102：一種組合，其包含治療有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽及一或多種額外之治療劑且視需要進一步包含醫藥上可接受之載劑，其中該額外之治療劑係獨立地選自抗炎劑、免疫調節劑、免疫抑制劑、細胞介素、非類固醇抗炎藥物(NSAID)、抗瘧化合物、抗風濕化合物、B細胞活化因子(BAFF)之抑制劑、B淋巴細胞刺激劑(BLyS)之抑制劑及類固醇激素。藥理學及效用 本發明之化合物大體上係胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之抑制劑，且可因此適用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病。因此，本發明之化合物可適用於治療自體免疫疾病，其等包括全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群(Sjögren’s syndrome)、關節炎、類風濕性關節炎或牛皮癬。 本發明之化合物大體上係TLR7、TLR7及TLR8或TLR7及TLR8及TLR9之抑制劑且可因此適用於治療與TLR7活性、TLR7及TLR8活性或TLR7及TLR8及TLR9活性相關聯之自體免疫疾病。因此，本發明之化合物可適用於治療自體免疫疾病，其等包括全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 另外，本發明之化合物大體上係胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之抑制劑，且可因此適用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病。因此，本發明之化合物可適用於治療自體免疫疾病，其等包括全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 呈游離形式或呈醫藥上可接受之鹽形式之本發明之化合物顯示有價值之藥理學性質，例如，如本文提供之如指示之活體外及活體內測試，且因此經指示用於治療或用作研究化學品，例如，作為工具化合物。 因此，作為另一實施例，本發明提供本發明之化合物在治療中之用途，其中該治療係自體免疫疾病之治療，該自體免疫疾病可藉由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之抑制進行治療。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 在另一實施例中，該治療係自體免疫疾病之治療，該自體免疫疾病可藉由TLR7、TLR7及TLR8或TLR7及TLR8及TLR9之抑制進行治療。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 另一實施例，本發明提供本發明之化合物在治療中之用途，其中該治療係自體免疫疾病之治療，該自體免疫疾病可藉由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路及其任何組合之抑制進行治療。在另一實施例中，該自體免疫疾病係選自諸如全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬之自體免疫疾病。 在另一實施例中，本發明提供治療自體免疫疾病之方法，該自體免疫疾病係藉由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之抑制進行治療，其中該方法包括投與治療上可接受之量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 在另一實施例中，本發明提供治療自體免疫疾病之方法，該自體免疫疾病係藉由TLR7、TLR7及TLR8或TLR7及TLR8及TLR9之抑制進行治療，其中該方法包括投與治療上可接受之量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 在另一實施例中，本發明提供治療自體免疫疾病之方法，該自體免疫疾病係藉由胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之抑制進行治療，其中該方法包括投與治療上可接受之量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 因此，作為另一實施例，本發明提供式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物在製造用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病之藥劑中之用途。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 在另一實施例中，本發明提供式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物在製造用於治療與TLR7、TLR7及TLR8或TLR7及TLR8及TLR9之活性相關聯之自體免疫疾病之藥劑中之用途。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 作為另一實施例，本發明提供式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物在製造用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或任何組合之活性相關聯之自體免疫疾病之藥劑中之用途。在另一實施例中，該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 本發明之化合物之用途及本發明之治療方法之某些態樣係提供於額外之枚舉型實施例之下列列表中。將認知各實施例中規定之特徵可與其他規定特徵組合以提供本發明之其他實施例。 實施例103：一種用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，藉此治療該疾病。 實施例104：一種用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，及其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例105：一種用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，藉此治療該疾病。 實施例106：一種用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病之方法，其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，及其中該自體免疫係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例107：一種用於治療與以下相關聯之自體免疫疾病之方法 i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性， 其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，藉此治療該疾病。 實施例108：一種用於治療與以下相關聯之自體免疫疾病之方法 i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性， 其中該方法包括向有此治療需求之個體投與有效量之式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，及其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例109：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9之活性相關聯之自體免疫疾病。 實施例110：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例111：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病。 實施例112：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例113：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與以下相關聯之自體免疫疾病 i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性， 其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例114：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9之活性相關聯之自體免疫疾病。 實施例115：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)或其任何組合(包括(但不限於)TLR7/8、TLR7/8/9、TLR7/9及TLR8/9)之活性相關聯之自體免疫疾病，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例116：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病。 實施例117：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與胞內體類鐸受體(例如，TLR7、TLR8或TLR9)通路或其任何組合之活性相關聯之自體免疫疾病，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。 實施例114：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽，其用於治療與以下相關之疾病 i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性， 其中該疾病係自體免疫疾病。 實施例115：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽在製造用於治療其中與TLR7活性、TLR7及TLR8活性或TLR7及TLR8及TLR9活性相關聯之自體免疫疾病之藥劑中之用途。 實施例116：一種式(A)、式(I)、式(II)、式(Ia至Ip)或式(IIa至IIk)化合物或其醫藥上可接受之鹽在製造用於治療自體免疫疾病之藥劑中之用途，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。分析 本發明之化合物係在下列段落中描述之分析中進行分析。測試化合物製備 通常將化合物連續稀釋(1/3)於DMSO中並接種於無菌384孔組織培養盤上且儲存直至準備使用。通常將各十點稀釋平行一式三份進行接種。在人類 PBMC 中之 TLR7 、 TLR8 及 TLR9 拮抗物分析 PBMC 分離 在分析之早上，在書面知情同意下自正常人供體收集新鮮血液至肝素化注射器中。將血液稀釋於RPMI-1640培養基中並藉由於Ficoll墊上離心(800g 15’ 0加速，0制動)自紅血球分離白血球。藉由在PBS+5% HI-FBS及1 mm EDTA中之一系列低速離心(1000RPM 10’)自血小板分離外周血單核細胞(PBMC)。將經純化之PBMC重懸浮於分析培養基(以5% HI-FBS、10 mm HEPES、50 μM β-巰基乙醇及100 mG/L盤尼西林/鏈黴素混合物補充之RPMI-1640 w Glutamax (Invitrogen))中。在血細胞計數器上計數活PBMC並保持於冰上直至準備接種。促效劑治療批量轉染 使4 X濃度(針對TLR8或TLR7分析，分別4 μg/ml或40 μg/ml)之TLR7/8促效劑ssRNA40 (IDT)在分析培養基與10% DOTAP (Roche)複合30分鐘，然後添加至PBMC懸浮液(5百萬個細胞/ml)。添加後，ssRNA40於受TLR7/8刺激之PBMC懸浮液中之最終濃度針對TLR8分析係1 µg/ml，及針對TLR7分析係10 µg/ mL。最終DOTAP濃度係2.5%。 經稀釋之PBMC (5百萬個細胞/ml)係用4 X TLR9促效劑ODN2216 (Invivogen)處理。ODN2216於受TLR9刺激之PBMC懸浮液中之最終濃度係0.3 µm。PBMC 接種及化合物處理 以150,000個細胞/孔將受促效劑刺激之PBMC接種於經化合物處理之384孔盤上。將未受刺激之PBMC作為對照接種於各盤上。接種體積係每孔40 µL。各孔中之DMSO濃度係0.25%。 每個分析中包括無化合物之具有ssRNA40及ODN2216之滴定之各別盤以量測各供體之PBMC製劑之促效劑反應。將分析盤在組織培養培養器(37℃，5%CO2 )中放置14至16小時。在此培養後，將該等盤離心並儲存於-20℃下直至對其等進行分析。針對 TLR8 活性之 IL-6 TR-FRET 分析： 1)使用Cisbio Human IL-6套組，20,000次測試(62TNFPEC)，及GNF High-Base TC 384孔盤(cat # 789163G)； 2)將抗-TIL-6穴狀化合物結合物及抗-IL-6 XL665結合物1:20稀釋於復水緩衝劑中； 3)製備3 µL/孔抗-IL-6穴狀化合物結合物及3 µL/孔抗-IL-6 XL665結合物之1:1混合物； 4)將6 µL/孔HTRF稀釋主混合物(mastermix)添加至於淺孔微孔盤(proxiplate)中之6 µL經轉移之上清液樣本； 5)在室溫下於黑暗中將該等盤培養3小時；及 6) IL-6產生之濃度係使用具有HTRF設定及比例讀數：(XL665發射/Eu穴狀化合物發射)X10,000之Envision盤讀數器(665 nm (發射)/590 nm (激發))進行量測。針對 TLR7 或 TLR9 活性之 IFN α 2b AlphaLISA 分析 在將分析盤解凍後，將6 µL上清液樣本轉移至低體積AlphaPlate 384SW (Perkin-Elmer)。IFNα於上清液中之濃度係使用IFNα2b AlphaLISA分析(Perkin-Elmer: AL297F)進行量測。首先使用實驗室自動裝置添加3 µL IFNα受體珠/生物素化抗體溶液。在培養一小時後，添加3 µL鏈黴親和素受體珠溶液。在黑暗中將含有此混合物之盤培養一小時並在由製造商設定之讀數參數下於適當之盤讀數器上進行讀數。(Envision, EnSpire: Perkin-Elmer)。THP-1 TLR8 拮抗物 TNF αTR-FRET 分析 基於細胞之分析： 1)將THP-1細胞培養於具有10% FBS、10 mm HEPES、1 mm丙酮酸鈉、1%盤尼西林-鏈黴素L-麩醯胺酸及1%非必需胺基酸之RPMI 1640中； 2) 將於分析培養基中之3組不同傳代之THP-1細胞匯集，計數及重懸浮於與培養培養基相同但具有5% FBS之培養基中； 3)將細胞稀釋至100,000個細胞/孔(30 µL/孔)並以10 µl/孔將R848促效劑在培養基中稀釋至25 µm； 4)組合細胞及促效劑稀釋並以40 µL/孔添加至含有於DMSO中之測試化合物之384孔平底格雷納(Greiner)分析盤，所述測試化合物係以8 mM最高劑量及10點1:3連續稀釋- 10 µm最終最高劑量以每孔50 nL預點樣； 5)在37℃下以5% CO2 將該等盤培養整夜，歷時18至20小時； 6)然後在室溫下以1000 rpm將該等盤離心2分鐘； 7)將10 µL/孔之上清液轉移至384孔低體積白色格雷納淺孔微孔盤；及 8) TNFα濃度係使用下文描述之TR-FRET分析進行量測。TNF α TR-FRET 分析： 1)使用Cisbio Human TNFα套組，20,000次測試(62TNFPEC)及格雷納Bio-One LIA-白色TC 384孔小體積盤(cat # 784080)； 2)將抗-TNFα穴狀化合物結合物及抗-TNFα XL665結合物1:20稀釋於復水緩衝劑中； 3)製備5 µL/孔抗-TNFα穴狀化合物結合物及5 µL/孔抗-TNFα XL665結合物之1:1混合物； 4)將10 µL/孔HTRF稀釋主混合物添加至於淺孔微孔盤中之10 µL經轉移之上清液樣本； 5)在室溫下於黑暗中將該等盤培養3小時；及 6) TNFα產生之濃度係使用Envision盤讀數器(665 nm (發射)/590 nm (激發))進行量測。 呈游離形式或呈醫藥上可接受之鹽形式之本發明之各種化合物顯示(例如)如由表7中呈現之分析結果指示之藥理學性質。IC50 值係作為所討論之測試化合物之在基線與最大反應之間之反應之濃度給定。表7中之虛線(---)意指未進行測試。表 7 ：分析結果 表 8 ：分析結果 應瞭解本文描述之實例及實施例係僅出於說明目的且熟習此項技術者可依此進行各種修改或改變且該等各種修改或改變欲包括於本申請案之精神及範圍內及隨附申請專利範圍之範疇內。Various enumerated embodiments of the invention are described herein. Features specified in the various embodiments may be combined with other specified features to provide further embodiments of the invention.definition The term "C" as used herein1 -C6 "Alkyl" means a fully saturated branched or straight chain hydrocarbon having from 1 to 6 carbon atoms. "C1 -C6 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl and hexyl . The term "C" as used herein1 -C6 Alkoxy" refers to the group -O-C1 -C6 Alkyl, where "C1 -C6 Alkyl" is as defined herein. "C1 -C6 Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, third butoxy, N-pentyloxy, isopentyloxy and hexyloxy. The term "cycloalkyl" as used herein refers to a saturated, monocyclic, fused bicyclic, fused tricyclic or bridged polycyclic ring system. Non-limiting examples of fused bicyclic or bridged multiple annular ring systems include bicyclo [1.1.1] pentane, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [3.1.1] heptane Bicyclo[3.2.1]octane, bicyclo[2.2.2]octane and adamantyl. As used herein, the term "C3 -C6 "Cycloalkyl" means a saturated monocyclic group having at least 3 and up to 6 carbon atoms. These "C3 -C6 Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C" as used herein1 -C6 "Haloalkyl" means individual "C as defined herein"1 -C6 Alkyl", where the "C1 -C6 At least one of the hydrogen atoms of the alkyl group is replaced by a halogen atom. These C1 -C6 Haloalkyl group can be single C1 -C6 Haloalkyl, of which C1 -C6 The haloalkyl group has one iodine, one bromine, one chlorine or one fluorine. In addition, these C1 -C6 Haloalkyl group can be two C1 -C6 Haloalkyl, of which C1 -C6 The haloalkyl group may have two halogen atoms independently selected from the group consisting of iodine, bromine, chlorine or fluorine. In addition, these C1 -C6 Haloalkyl group can be poly C1 -C6 Haloalkyl, of which C1 -C6 A haloalkyl group can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such poly C1 -C6 Haloalkyl group can be perhalogenated C1 -C6 Haloalkyl, individual C1 -C6 All of the hydrogen atoms of the alkyl group have been replaced by halogen atoms and the halogen atoms may be the same or a combination of different halogen atoms. C1 -C6 Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloro Methyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "halo" or "halogen" as used herein means fluoro, chloro, bromo and iodo. The term "5 to 6 membered heteroaryl" as used herein refers to a monocyclic aromatic ring structure having 5 or 6 ring members, wherein 1 to 3 ring members are independently selected from heteroatoms N, O and S. . Non-limiting examples of 5- to 6-membered heteroaryl include 2- or 3-furanyl; 2- or 3-thienyl; 1-, 2- or 3-pyrrolyl; 2-, 4- or 5-oxazole 2-, 4- or 5-thiazolyl; 1-, 2-, 4- or 5-imidazolyl; 1-, 3-, 4- or 5-pyrazolyl; 3-, 4- or 5- Isoxazolyl; 3-, 4- or 5-isothiazolyl; 4- or 5-1,2,3-oxadiazolyl; 4- or 5-1,2,3-triazolyl; 2- Or 5-1,3,4-thiadiazolyl; 2-, 3- or 4-pyridyl; 3-, 4-, 5- or 6-pyridazinyl; 2-, 4-, 5- or 6 - Pyrimidinyl and 2- or 3-pyrazinyl. The term "heteroatom" as used herein refers to a nitrogen (N), oxygen (O) or sulfur (S) atom. The term "4- to 6-membered heterocycloalkyl" as used herein refers to a monocyclic ring structure having 4 to 6 ring members, wherein one or both of the ring members are independently selected from N, NH, NR.16 , O or -S-, where R16 Department C1 -C6 alkyl. In a preferred embodiment, the 4 to 6 membered heterocycloalkyl group has a single toroidal ring structure of 4 to 6 ring members, wherein one or both of the ring members are independently selected from N, NH, NR.16 And O, where R16 Department C1 -C6 alkyl. As used herein, non-limiting examples of 4- to 6-membered heterocycloalkyl include azetidinyl, azetidin-1-yl, azetidin-2-yl, azetidine 3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietane, sulphur Heterocyclobutan-2-yl, thietane-3-yl, thietane-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidine- 3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothiophenyl, Tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, tetrahydrothiophen-4-yl, tetrahydrothiophen-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, Piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropentanyl, tetrahydropyran-2-yl, tetrahydropyran-3- , tetrahydropyran-4-yl, tetrahydropentan-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3 -yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl Piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, Morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, sulfur? Benz-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxathiolanyl, oxathiane-2-yl, oxygen Thiacyclo-3-yl, oxathiane-5-yl, oxathiane-6-yl, dithiaalkyl, dithian-2-yl, dithiane-3 -yl,dithiane-5-yl,dithiane-6-yl,dioxolanyl,dioxol-2-yl,dioxol-4-yl,dioxole Penta-5-yl, oxathiolanyl, oxathiane-2-yl, oxathiacyclo-3-yl, oxathiacyclo-4-yl, oxathia Cyclohexane-5-yl, dithiolanyl, dithialan-2-yl, dithiolan-4-yl, dithiolane-5-yl, pyridyl An azolidinyl group, a pyrazin-1-yl group, a pyrazolidine-2-yl group, a pyrazolidine-3-yl group, a pyrazolidine-4-yl group, and a pyrazolidine-5-yl group. The term "hydroxy" as used herein refers to an -OH group. The term "sideoxy" as used herein refers to a =O group. The term "autoimmune disease" or "autoimmune disorder" as used herein refers to an uncontrolled attack on the body's own tissues and organs (autoimmune), producing an inflammatory response and other serious symptoms. Disease of disease. Non-limiting examples of autoimmune diseases include idiopathic thrombocytopenic purpura, hemolytic anemia, systemic lupus erythematosus, cutaneous lupus, discoid lupus, rheumatoid arthritis (RA), multiple sclerosis (MS) , systemic sclerosis, immune-mediated or type 1 diabetes, immune-mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammation Intestinal disease, Crohn's disease, Graves' disease, psoriasis, autoimmune thyroid disease, Hashimoto's disease, Hashimoto's thyroiditis, polymyositis, skin Myositis, CREST syndrome, Goodpasture's syndrome, mixed connective tissue disease, myasthenia gravis, nystagmus, phakogene uveitis, chronic invasive hepatitis, primary bile Spontaneous cirrhosis, autoimmune hemolytic anemia, Werlof disease, vitiligo vulgaris, Behcet's disease, collagen disease, uveitis, rest Glen syndrome, autoimmune myocarditis, autoimmune liver disease, autoimmune gastritis, pemphigus, Guillain-Barre syndrome, atherosclerosis, inflammatory bowel disease, tonicity Spondylitis, idiopathic thrombocytopenia, nodular polyarteritis, primary biliary cirrhosis, sarcoidosis, sclerosing cholangitis, multiple arteritis (Takayasu's arteritis), temporal arteritis, Wegener's granulomatosis (Wegener's) Granulomatosis) and HTLV-1 related myelopathy. The term "combination" or "pharmaceutical combination" as used herein means a product derived from a combination of fixed or non-fixed combinations of at least one active ingredient and comprising the active ingredient. The term "fixed combination" means that the active ingredient (by way of example) a compound of the invention and one or more additional therapeutic agents are administered to the individual simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient (by way of example of a compound of the invention and one or more additional therapeutic agents) is administered as a separate entity to the individual simultaneously, concurrently or sequentially, without a specific time limit, Wherein it is administered to provide a therapeutically effective concentration of the active ingredient in the body of the individual. The latter is also suitable for the treatment of mixtures, for example the administration of three or more active ingredients. The term "composition" or "pharmaceutical composition" as used herein means a compound of the invention with at least one and optionally more than one other pharmaceutically acceptable chemical component (such as a carrier, stabilizer, diluent, A mixture of dispersing agents, suspending agents, thickening agents and/or excipients. As used herein, the term "inhibiting" refers to a reduction or inhibition of a given condition, symptom or disorder or disease or a significant decrease in the baseline activity of a biological activity or process. The term "optical isomer" or "stereoisomer" as used herein refers to any of the various stereoisomeric configurations that may exist for a given compound of the invention and includes geometric isomers. It will be appreciated that the substituents may be attached to the palm center of the carbon atom. The term "pair of palm" refers to a molecule that has non-overlapping properties to its mirror image partner, and the term "non-paired" refers to a molecule that overlaps with its mirror partner. Accordingly, the invention includes enantiomers, diastereomers or racemates of the compounds. An "enantiomer" is a pair of stereoisomers that are non-superimposable mirror images of each other. The 1:1 mixture of enantiomers is a "racemic" mixture. This term applies to the specified racemic mixture as needed. "Diastereomers" are stereoisomers having at least two asymmetric atoms, but which are not mirror images of one another. The absolute stereochemistry is based on the Cahn-Ingold-Prelog R-S system. When the compound is a pure enantiomer, the stereochemistry at each pair of palmitic carbons can be specified by R or S. Analyzed compounds of unknown absolute configuration may be designated as (+) or (-) depending on the direction in which the plane polarized light is rotated (right-handed or left-handed) at the wavelength of the sodium D-line. Certain compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or (S)-. The term "pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (eg, antibacterial, antifungal), isotonic agents, Absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrating agents, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (See, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). It is also contemplated for use in therapeutic or pharmaceutical compositions, except where any conventional carrier is incompatible with the active ingredient. The term "pharmaceutically acceptable salt" as used herein refers to a salt which does not abrogate the biological activity and properties of the compounds of the present invention and which does not cause significant irritation to the individual to which it is administered. The term "individual" as used herein encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. Typically, the system is human, and may have been diagnosed as being required to target endogenous receptors (eg, TLR7, TLR8, or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8) /9, TLR7/9 and TLR8/9) are associated with the activity of a disease or disorder associated with the activity of an intracellular somatosensory receptor (eg, TLR7, TLR8 or TLR9) pathway and any combination thereof . The term "an individual in need of such treatment" means an individual who would benefit from the biological, pharmaceutical or quality life of the treatment. The term "therapeutically effective amount" as used herein refers to a biological or pharmaceutical response that will elicit an individual (eg, a decrease in the activity of an enzyme or protein or amelioration or alleviation of a condition, amelioration of a condition, slowing or delaying the progression of a disease, or prevention of a disease, etc.) The amount of the compound of the invention. In one non-limiting embodiment, the term "therapeutically effective amount" means that a compound of the invention is effective (1) at least partially alleviating, inhibiting, preventing, and/or alleviating (i) by intracellular body when administered to an individual. A purine-like receptor (eg, TLR7, TLR8, or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) are mediated or by intracellular bodies A purine receptor (eg, TLR7, TLR8, or TLR9) pathway and any combination thereof mediated or (ii) with an intracellular receptor steroid receptor (eg, TLR7, TLR8, or TLR9), and any combination thereof (including but not limited to ) TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) are associated with or associated with the intracellular steroid receptor (eg, TLR7, TLR8, or TLR9) pathway and any combination thereof, or (iii) Activity by endosome receptors (eg, TLR7, TLR8, or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) (normal Or abnormally characterized condition or disorder or disease; (2) reducing or inhibiting endogenous steroid receptors (eg, TLR7, TLR8 or TLR9) and any combination thereof (including but not limited to, TLR7/8, Activity of TLR7/8/9, TLR7/9 and TLR8/9); or (3) reduction or suppression Endosomal toll-like receptor (e.g., TLR7, TLR8 or TLR9) and any combination thereof (including (but not limited to) TLR7 / 8, TLR7 / 8/9, TLR7 / 9 and TLR8 / 9) the amount of expression. In another non-limiting embodiment, the term "therapeutically effective amount" means that a compound provided herein is effective (at least in part) in reducing or inhibiting intracellular bodies when administered to a cell or tissue or non-cellular biological material or medium.铎 Receptor (eg, TLR7, TLR8, or TLR9) and any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) activity or inhibition of intracellular steroids The amount of activity of the receptor (eg, TLR7, TLR8 or TLR9) pathway and any combination thereof. The terms "TLR7 inhibitor", "TLR7 antagonist", "inhibitor of TLR7" or "inhibitor of TLR7" as used herein mean a compound of the invention which inhibits steroid receptor 7 (TLR7). The compounds of the invention inhibit both type I interferons and pro-inflammatory interleukins downstream of TLR7. The terms "TLR8 inhibitor", "TLR8 antagonist", "inhibitor of TLR8" or "inhibitor of TLR8" as used herein mean a compound of the invention which inhibits steroid receptor 8 (TLR8). The terms "TLR7 and TLR8 inhibitors", "TLR7 and TLR8 antagonists", "inhibitors of TLR7 and TLR8" or "inhibitors of TLR7 and TLR8" as used herein mean inhibitory receptor 7 (TLR7) and A compound of the invention which is a terpenoid receptor 8 (TLR8). The compounds of the present invention inhibit type I interferons downstream of TLR7 and proinflammatory interleukins downstream of NF-KB in TLR7 and TLR8 signaling. "TLR7 and TLR8 inhibitors" or "TLR7 and TLR8 antagonists" may also be referred to by the term "TLR7/8 antagonist". The terms "TLR7, TLR8 and TLR9 inhibitors", "TLR7, TLR8 and TLR9 antagonists", "inhibitors of TLR7, TLR8 and TLR9" or "inhibitors of TLR7, TLR8 and TLR9" as used herein refer to inhibition classes. A compound of the invention of 铎 receptor 7 (TLR7), 铎 receptor 8 (TLR8) and 铎 receptor 9 (TLR9). The compounds of the present invention inhibit type I interferons downstream of TLR7 and proinflammatory interleukins downstream of NF-KB in TLR7 and TLR8 signaling. "TLR7 and TLR8 and TLR9 inhibitors" or "TLR7 and TLR8 and TLR9 antagonists" may also be referred to by the term "TLR7/8/9 antagonist". In one embodiment, the term "treating" of any disease or disorder refers to alleviating the disease or disorder (ie, slowing or preventing or reducing the progression of at least one of the disease or its clinical symptoms). In another embodiment, "treating" refers to alleviating or alleviating at least one physical parameter, including those that are not identifiable by the patient. In yet another embodiment, "treating" refers to physically (eg, identifiable stabilization of symptoms), physiological (eg, stabilization of physical parameters), or both, modulating the disease or disorder. In yet another embodiment, "treating" refers to preventing or delaying the onset or progression or progression of the disease or disorder. The compound names provided herein were obtained using ChemDraw Ultra version 12.0 (CambridgeSoft®) or JChem version 5.3.1 (ChemAxon). Unless otherwise specified herein, the terms "compounds of the present invention", "compounds of the invention" or "compounds provided herein" refer to formula (A), formula ( I), a compound of the formula (II) and its subformulae (such as the compounds of the formulae (Ia to Ip) and (IIa to IIk)) and pharmaceutically acceptable salts, stereoisomers (including diastereomers and Enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions) and intrinsically formed moieties. The terms "a", "an", "the" and the like are used in the context of the invention (especially in the context of the accompanying claims), unless otherwise indicated herein. It should be considered to cover both singular and plural.Compound of the invention The compound of the present invention is a compound having the structure of the formula (A) or a pharmaceutically acceptable salt thereof:Formula (A) where RA system,,,,,,,,,or; L system-CH2 -or-CH2 CH2 -; Y1 Department-CH2 -or-CH2 CH2 -; Y2 Department-CH2 -or-CH2 CH2 -; Y3 Department-CH2 -, -XCH2 -or-CH2 X-; X-CH2 -or O; R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CH2 )n OR9 , -NHC(=O)OR9 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 , NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n N(R8 )2 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )m C(=O)R6 -NHR6 , -NR5 R6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -N(R6 R8 ), -NH(C(R)9 )2 )n R10 , -NR9 C(=O)OR11 , -NH(CH2 )n R6 , -NH (CHR9 )n R6 , -N(R6 )2 , -NHC(=O)(CH2 )n N (CD3 )2 , -NH (CHR9 )n CH2 OR9 -NHCH2 (CHR9 )n OR9 , -NH (CHR9 )n OR9 , -NR9 (CH2 )n OR9 -NHCH2 (C(R9 )2 )n OR9 , -OR9 , -NR9 C(=O)R5 , -NR9 C(=O)(CH2 )n R5 , -NR9 C(=O)OR5 , -NHS(=O)2 R5 , -NHC(=O)(CH2 )n NR9 C(=O)R5 , -NHC(=O)(CH2 )n NR9 S(=O)2 R5 ,,, 8-oxa-3-azabicyclo[3.2.1]octyl, 5 to 6 membered heteroaryl having 1 to 3 ring members independently selected from N, O and S and independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or have 1 to 2 R7 Group substitution; R2 H, C1 -C6 Alkyl, C1 -C6 Haloalkyl or 1 to 2 R15 Group substituted C1 -C6 Alkyl; R3 H, C1 -C6 Alkyl, -CD3 Or after 1 to 2 R10 Group substituted benzyl; R4 H, NH2 , C1 -C6 Alkyl, halo or 0 to 2 R18 Group substituted phenyl; each R5 Independently selected from C1 -C6 Alkyl, -CD3 And - (CH2 )n OR9 ; R6 Department C3 -C6 Cycloalkyl, oxa-3-azabicyclo[3.2.1]octane or having independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or have 1 to 2 R12 Group substitution; each R7 Independently selected from C1 -C6 Alkyl, halo, hydroxy, pendant oxy and C substituted by 1 to 3 -OH1 -C6 Alkyl; each R8 Independently selected from C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 Alkyl; R10 Department C1 -C6 Alkoxy or C3 -C6 Cycloalkyl; R11 Unsubstituted or 1 to 3 C1 -C6 Alkyl substituted C3 -C6 Cycloalkyl; each R12 Independently selected from C1 -C6 Alkyl, hydroxy, halo and C substituted by 1 to 3 -OH1 -C6 Alkyl; R13 H or C1 -C6 Alkyl; R14 H or C1 -C6 Alkyl; R15 Department-NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n N(R8 )2 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR8 , -N(R6 R8 ), -NH(C(R)9 )2 )n R10 , -NR9 C(=O)OR11 , -NH (CHR9 )n R6 , -N(R6 )2 , -N (CD3 )2 , -NH (CHR9 )n OR9 Or -NHCH2 (C(R9 )2 )n OR9 ; each R16 Department C1 -C6 Alkyl; each R17 Lines are independently selected from H and C1 -C6 Alkyl; each R18 Is independently selected from halo, -CN, C1 -C6 Alkoxy or C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Certain aspects and examples of the compounds of the present invention are provided in the following list of additional enumerated examples. Features specified in the various embodiments may be combined with other specified features to provide further embodiments of the invention. Example 1: A compound having the structure of formula (A) is a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: Formula (I) Formula (II). Where Y1 , Y2 , Y3 , L, R1 , R2 And RA It is as defined herein for the compound of formula (A). Example 2: A compound having the structure of formula (A) or formula (I) has the formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula a compound of the formula (Ig), formula (Ih), formula (Ii), formula (Ij) or formula (Ik) or a pharmaceutically acceptable salt thereof:,, formula (Ia), formula (Ib),Formula (Ic) (Id),Formula (Ie) (If),Formula (Ig) (Ih),Formula (Ii) (Ij), (Ik) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 , R13 , R14 And R18 It is as defined herein for the compound of formula (A). Example 3: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ia) or formula (Ig) or a pharmaceutically acceptable salt thereof: Formula (Ia) Formula (Ig) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R13 It is as defined herein for the compound of formula (A). Example 4: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ib), formula (Ic) or formula (Id) or a pharmaceutically acceptable salt thereof:,Formula (Ib) Formula (Ic)Formula (Id) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R13 It is as defined herein for the compound of formula (A). Example 5: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ie) or formula (Ih) or a pharmaceutically acceptable salt thereof:,Formula (Ie) Formula (Ih) where Y1 , Y2 , Y3 , L, R1 , R2 And R3 It is as defined herein for the compound of formula (A). Example 6: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (If) or a pharmaceutically acceptable salt thereof:Formula (If) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R14 It is as defined herein for the compound of formula (A). Example 7: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ii) or a pharmaceutically acceptable salt thereof:Formula (Ii) where Y1 , Y2 , Y3 , L, R1 , R2 , R4 And each R13 It is as defined herein for the compound of formula (A). Example 8: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ij) or formula (Ik) or a pharmaceutically acceptable salt thereof: Formula (Ij) where (Ik) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 And R18 It is as defined herein for the compound of formula (A). Example 9: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Im) or a pharmaceutically acceptable salt thereof:Formula (Im) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 And R4 It is as defined herein for the compound of formula (A). Example 10: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (In) or a pharmaceutically acceptable salt thereof:Formula (In) where Y1 , X, L, R1 , R2 , R3 And R4 It is as defined herein for the compound of formula (A). Embodiment 11: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Io) or a pharmaceutically acceptable salt thereof:Formula (Io) where L, R1 , R2 , R3 And R4 It is as defined herein for the compound of formula (A). Embodiment 12: A compound having the structure of formula (A) or formula (I) is a compound having the structure of formula (Ip) or a pharmaceutically acceptable salt thereof:Formula (Ip) where R1 It is as defined herein for the compound of formula (A). Example 13: A compound having the structure of formula (A) or formula (II) has formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula (IIf), formula a compound of the formula (IIg), formula (IIh), formula (IIi), formula (IIj) or formula (IIk) or a pharmaceutically acceptable salt thereof:,, formula (IIa), formula (IIb),Formula (IIc) (IId),Formula (IIe) (IIf),Formula (IIg) (IIh),Formula (IIi) (IIj), (IIk) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 , R13 , R14 And R18 It is as defined herein for the compound of formula (A). Embodiment 14: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIa) or formula (IIg) or a pharmaceutically acceptable salt thereof: Formula (IIa) Formula (IIg) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R13 It is as defined herein for the compound of formula (A). Embodiment 15: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIb), formula (IIc) or formula (IId) or a pharmaceutically acceptable salt thereof:,Formula (IIb) (IIc)Formula (IId) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R13 It is as defined herein for the compound of formula (A). Embodiment 16: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIe) or formula (IIh) or a pharmaceutically acceptable salt thereof:,Formula (IIe) Formula (IIh) where Y1 , Y2 , Y3 , L, R1 , R2 And R3 It is as defined herein for the compound of formula (A). Embodiment 17: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIf) or a pharmaceutically acceptable salt thereof:Formula (IIf) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 And R14 It is as defined herein for the compound of formula (A). Embodiment 18: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIi) or a pharmaceutically acceptable salt thereof:Formula (IIi) where Y1 , Y2 , Y3 , L, R1 , R2 , R4 And each R13 It is as defined herein for the compound of formula (A). Embodiment 19: A compound having the structure of formula (A) or formula (II) is a compound having the structure of formula (IIj) or formula (IIk) or a pharmaceutically acceptable salt thereof: Formula (IIj) where (IIk) where Y1 , Y2 , Y3 , L, R1 , R2 , R3 And R18 It is as defined herein for the compound of formula (A). Example 20: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L-system-CH2 -or-CH2 CH2 -; Y1 Department-CH2 -or-CH2 CH2 -; Y2 Department-CH2 -or-CH2 CH2 -; Y3 Department-CH2 -or-XCH2 -; X-CH2 -or O; R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CH2 )n OR9 , -NHC(=O)OR9 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n N(R8 )2 , -NHC(=O)(CHR9 )n NHR8 , -NR9 C(=O)OR11 , -NHC(=O)(CH2 )n N (CD3 )2 , -NR9 C(=O)R5 , -NR9 C(=O)(CH2 )n R5 , -NR9 C(=O)OR5 , -NHS(=O)2 R5 , -NHC(=O)(CH2 )n NR9 C(=O)R5 Or -NHC(=O)(CH2 )n NR9 S(=O)2 R5 ; R2 H, C1 -C6 Alkyl or C1 -C6 Haloalkyl; R3 H, C1 -C6 Alkyl or -CD3 ; R4 H, NH2 , C1 -C6 Alkyl or halo; each R5 Independently selected from C1 -C6 Alkyl, -CD3 And - (CH2 )n OR9 ; R6 Department C3 -C6 Cycloalkyl or having independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or have 1 to 2 R12 Group substitution; each R8 Independently selected from C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 Alkyl; R11 Unsubstituted or 1 to 3 C1 -C6 Alkyl substituted C3 -C6 Cycloalkyl; each R12 Independently selected from C1 -C6 Alkyl, hydroxy, halo and C substituted by 1 to 3 -OH1 -C6 Alkyl; R13 H or C1 -C6 Alkyl; R14 H or C1 -C6 Alkyl; each R16 Department C1 -C6 Alkyl; each R17 Lines are independently selected from H and C1 -C6 Alkyl; each R18 Is independently selected from halo, -CN, C1 -C6 Alkoxy or C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Embodiment 21: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L system-CH2 -or-CH2 CH2 -; Y1 Department-CH2 -or-CH2 CH2 -; Y2 Department-CH2 -or-CH2 CH2 -; Y3 Department-CH2 -or-XCH2 -; X-CH2 -or O; R1 Department-NH(CH2 )n C(=O)R6 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )m C(=O)R6 , -NH(C(R9 )2 )n R10 , -NH(CH2 )n R6 , -NH (CHR9 )n R6 , -NH (CHR9 )n CH2 OR9 -NHCH2 (CHR9 )n OR9 , -NH (CHR9 )n OR9 , -NR9 (CH2 )n OR9 Or -NHCH2 (C(R9 )2 )n OR9 ; R2 H, C1 -C6 Alkyl or C1 -C6 Haloalkyl; R3 H, C1 -C6 Alkyl or -CD3 ; R4 H, NH2 , C1 -C6 Alkyl or halo; each R5 Independently selected from C1 -C6 Alkyl, -CD3 And - (CH2 )n OR9 ; R6 Department C3 -C6 Cycloalkyl or having independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or have 1 to 2 R12 Group substitution; each R8 Independently selected from C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 Alkyl; R10 Department C1 -C6 Alkoxy or C3 -C6 Cycloalkyl; each R12 Independently selected from C1 -C6 Alkyl, hydroxy, halo and C substituted by 1 to 3 -OH1 -C6 Alkyl; R13 H or C1 -C6 Alkyl; R14 H or C1 -C6 Alkyl; each R16 Department C1 -C6 Alkyl; each R17 Lines are independently selected from H and C1 -C6 Alkyl; each R18 Is independently selected from halo, -CN, C1 -C6 Alkoxy and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Embodiment 22: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L system-CH2 -or-CH2 CH2 -; Y1 Department-CH2 -or-CH2 CH2 -; Y2 Department-CH2 -or-CH2 CH2 -; Y3 Department-CH2 -or-XCH2 -; X-CH2 -or O; R1 Department-NHR6 , -NR5 R6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -N(R6 R8 ) or -N(R6 )2 ; R2 H, C1 -C6 Alkyl or C1 -C6 Haloalkyl; R3 H, C1 -C6 Alkyl or -CD3 ; R4 H, NH2 , C1 -C6 Alkyl or halo; each R5 Independently selected from C1 -C6 Alkyl, -CD3 And - (CH2 )n OR9 ; R6 Department C3 -C6 Cycloalkyl or having independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or have 1 to 2 R12 Group substitution; each R8 Independently selected from C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R12 Independently selected from C1 -C6 Alkyl, hydroxy, halo and C substituted by 1 to 3 -OH1 -C6 Alkyl; R13 H or C1 -C6 Alkyl; R14 H or C1 -C6 Alkyl; each R16 Department C1 -C6 Alkyl; each R17 Lines are independently selected from H and C1 -C6 Alkyl; each R18 Is independently selected from halo, -CN, C1 -C6 Alkoxy and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 23: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CH2 )n OR9 , -NHC(=O)OR9 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 , NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n N(R8 )2 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )m C(=O)R6 -NHR6 , -NR5 R6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -N(R6 R8 ), -NH(C(R)9 )2 )n R10 , -NR9 C(=O)OR11 , -NH(CH2 )n R6 , -NH (CHR9 )n R6 , -N(R6 )2 , -NHC(=O)(CH2 )n N (CD3 )2 , -NH (CHR9 )n CH2 OR9 -NHCH2 (CHR9 )n OR9 , -NH (CHR9 )n OR9 , -NR9 (CH2 )n OR9 -NHCH2 (C(R9 )2 )n OR9 , -OR9 , -NR9 C(=O)R5 , -NR9 C(=O)(CH2 )n R5 , -NR9 C(=O)OR5 , -NHS(=O)2 R5 , -NHC(=O)(CH2 )n NR9 C(=O)R5 Or -NHC(=O)(CH2 )n NR9 S(=O)2 R5 . Embodiment 24: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein, R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CH2 )n OR9 , -NHC(=O)OR9 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )m C(=O)R6 -NHR6 , -NR5 R6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -NR9 C(=O)OR11 , -NH(CH2 )n R6 , -N(R6 )2 , -NHC(=O)(CH2 )n N (CD3 )2 , -NH (CHR9 )n CH2 OR9 -NHCH2 (CHR9 )n OR9 , -NH (CHR9 )n OR9 , -NR9 (CH2 )n OR9 -NHCH2 (C(R9 )2 )n OR9 , -OR9 , -NR9 C(=O)R5 , -NR9 C(=O)OR5 , -NHS(=O)2 R5 , -NHC(=O)(CH2 )n NR9 C(=O)R5 Or -NHC(=O)(CH2 )n NR9 S(=O)2 R5 . Example 25: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CH2 )n OR9 , -NHC(=O)OR9 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n N(R8 )2 , -NHC(=O)(CHR9 )n NHR8 , -NR9 C(=O)OR11 , -NHC(=O)(CH2 )n N (CD3 )2 , -NR9 C(=O)R5 , -NR9 C(=O)(CH2 )n R5 , -NR9 C(=O)OR5 , -NHS(=O)2 R5 , -NHC(=O)(CH2 )n NR9 C(=O)R5 Or -NHC(=O)(CH2 )n NR9 S(=O)2 R5 . Embodiment 26: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -NH (CHR9 )n OR9 Or -NHCH2 (C(R9 )2 )n OR9 . Example 27: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 Or -NHR8 . Example 28: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 -NHR6 -NH2 , -N(R5 )2 -NHR5 Or -NHR8 . Embodiment 29: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Department-NH(CH2 )n C(=O)R6 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 , -NH (CHR9 )n OR9 Or -NHCH2 (C(R9 )2 )n OR9 . Example 30: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )m N(R5 )2 -NHR6 Or -NH2 . Example 31: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CHR9 )n R6 , -NH (CHR9 )n C(=O)R6 Or -NHR6 Example 32: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NH(CH2 )n C(=O)R6 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )m C(=O)R6 , -NH(C(R9 )2 )n R10 , -NH(CH2 )n R6 , -NH (CHR9 )n R6 , -NH (CHR9 )n CH2 OR9 -NHCH2 (CHR9 )n OR9 , -NH (CHR9 )n OR9 , -NR9 (CH2 )n OR9 Or -NHCH2 (C(R9 )2 )n OR9 . Example 33: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHR6 , -NR5 R6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -N(R6 R8 ) or -N(R6 )2 . Embodiment 34: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR8 , 8-oxa-3-azabicyclo[3.2.1]octyl,Or with independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Replacement of the group. Embodiment 35: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -NH (CHR9 )n OR9 -NHCH2 (C(R9 )2 )n OR9 , 8-oxa-3-azabicyclo[3.2.1]octyl,Or with independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Replacement of the group. Embodiment 36: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L system-CH2 -or-CH2 CH2 -; Y1 Department-CH2 -or-CH2 CH2 -; Y2 Department-CH2 -or-CH2 CH2 -; Y3 Department-CH2 -or-XCH2 -; X-CH2 -or O; R1 system,, -OR9 , 8-oxa-3-azabicyclo[3.2.1]octyl, 5 to 6 membered heteroaryl having 1 to 3 ring members independently selected from N, O and S or independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Group substitution; R2 H, C1 -C6 Alkyl or C1 -C6 Haloalkyl; R3 H, C1 -C6 Alkyl or -CD3 ; R4 H, NH2 , C1 -C6 Alkyl or halo; each R7 Independently selected from C1 -C6 Alkyl, halo, hydroxy, pendant oxy and C substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 Alkyl; R13 H or C1 -C6 Alkyl; R14 H or C1 -C6 Alkyl; each R16 Department C1 -C6 Alkyl; each R17 Lines are independently selected from H and C1 -C6 Alkyl; each R18 Is independently selected from halo, -CN, C1 -C6 Alkoxy and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 37: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 8-oxa-3-azabicyclo[3.2.1]octyl,, with independently selected from N, NH, NR16 And an unsubstituted 4 to 6 membered heterocycloalkyl group of 1 to 2 ring members of O or independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which have 1 to 2 R7 Replacement of groups, where each R7 Independently selected from C1 -C6 Alkyl, hydroxy and pendant oxy groups. Embodiment 38: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Is independently selected from N, NH, NR16 And an unsubstituted 4 to 6 membered heterocycloalkyl group of 1 to 2 ring members of O or independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which have 1 to 2 R7 Replacement of groups, where each R7 Independently selected from C1 -C6 Alkyl, hydroxy and pendant oxy groups. Example 39: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl or imidazolyl, or R1 Azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl or imidazolyl, which has 1 to 2 R7 Substituted, in which each R7 Independently selected from C1 -C6 Alkyl, hydroxy and pendant oxy groups. Embodiment 40: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Is independently selected from N, NH, NR16 And an unsubstituted 4 to 6 membered heterocycloalkyl group of 8- to 2 ring members, 8-oxa-3-azabicyclo[3.2.1]octyl,Or with independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which have 1 to 2 R7 Replacement of the group. Example 41: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Is independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Replacement of the group. Embodiment 42: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl. Embodiment 43: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R1 Azetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, each of which is 1 to 2 R7 Replacement of the group. Example 44: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 8-oxa-3-azabicyclo[3.2.1]octyl or. Embodiment 45: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 Department C3 -C6 A cycloalkyl group or an unsubstituted 4 to 6 membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH and O. Embodiment 46: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 A 4- to 6-membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH and O. Embodiment 47: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 Is independently selected from N, NH, NR16 And an unsubstituted 4 to 6 membered heterocycloalkyl group of 1 to 2 ring members of O. Embodiment 48: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 Is a 4 to 6 membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH and O, which is 1 to 2 R12 Replacement of groups, where each R12 Independently selected from C1 -C6 Alkyl, hydroxy and C substituted by 1 to 3 -OH1 -C6 alkyl. Embodiment 49: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 Is independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are 1 to 2 R12 Replaced by a group, each of which R12 Independently selected from C1 -C6 Alkyl, hydroxy and C substituted by 1 to 3 -OH1 -C6 alkyl. Embodiment 50: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 Department C3 -C6 Cycloalkyl. Example 51: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R6 A cyclobutyl, oxetanyl, piperidinyl, pyrrolidinyl, morpholinyl or azetidinyl group. Example 52: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R6 A cyclobutyl, oxetanyl, piperidinyl, pyrrolidinyl, morpholinyl or azetidinyl group, each of which is 1 to 2 R12 Replacement of groups, where each R12 Independently selected from C1 -C6 Alkyl, hydroxy and C substituted by 1 to 3 -OH1 -C6 alkyl. Embodiment 53: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R6 An oxetanyl group, a piperidinyl group, a pyrrolidinyl group, a morpholinyl group or an azetidinyl group. Example 54: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R6 A cyclobutyl group. Example 55: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein L system-CH2 -;Y1 Department-CH2 CH2 -;Y2 Department-CH2 CH2 -;Y3 Department-XCH2 -; and X-series-CH2 -or O. Example 56: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein L system-CH2 -;Y1 Department-CH2 CH2 -;Y2 Department-CH2 CH2 -;Y3 Department-XCH2 -; and X-series-CH2 -. Embodiment 57: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L system-CH2 -or-CH2 CH2 -;Y1 Department-CH2 -or-CH2 CH2 -;Y2 Department-CH2 -or-CH2 CH2 -;Y3 Department-CH2 -or-XCH2 -; and X-series-CH2 -or O. Example 58: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein L system-CH2 -;Y1 Department-CH2 -;Y2 Department-CH2 -;Y3 Department-CH2 -; and X-series-CH2 -. Embodiment 59: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein the L system-CH2 -;Y1 Department-CH2 -;Y2 Department-CH2 CH2 -;Y3 Department-XCH2 -; and X-series-CH2 -or O. Example 60: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein L system-CH2 -;Y1 Department-CH2 -;Y2 Department-CH2 CH2 -;Y3 Department-XCH2 -; and X-series-CH2 -. Embodiment 61: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R2 Department C1 -C6 Alkyl; R3 Department C1 -C6 Alkyl and R4 Department C1 -C6 alkyl. Example 62: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R2 Methyl; R3 Methyl and R4 Is a methyl group. Example 63: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R2 H, C1 -C6 Alkyl or C1 -C6 Haloalkyl. Embodiment 64: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R2 H or C1 -C6 alkyl. Embodiment 65: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R3 H, C1 -C6 Alkyl or -CD3 . Embodiment 66: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R3 H or C1 -C6 alkyl. Embodiment 67: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R4 H, NH2 , C1 -C6 Alkyl or halo. Embodiment 68: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R4 H, NH2 Or C1 -C6 alkyl. Example 69: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R4 H or C1 -C6 alkyl. Embodiment 70: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R5 Independently selected from C1 -C6 Alkyl and -(CH2 )n OR9 . Embodiment 71: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R5 Independently selected from C1 -C6 Alkyl and -CD3 . Embodiment 72: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R5 Is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, -CD3 , -CH2 CH2 OCH2 CH3 And -CH2 CH2 OCH3 . Embodiment 73: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R7 They are independently selected from the group consisting of methyl, ethyl and pendant oxy groups. Embodiment 74: A compound of the formula (I), formula (Ia), formula (Ib) and formula (Ic) wherein each R8 Independently selected from C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 alkyl. Embodiment 75: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R8 Lines are independently selected from -CH2 CHF2 , -CH2 CF3 , -CH(CH3 )CH2 OH, -CH2 C(CH3 )2 OCH3 , -CH2 CH2 OCH3 , CH2 CH2 OCH2 CH3 And -CH2 C(CH3 )2 OH. Embodiment 76: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R9 Lines are independently selected from H and C1 -C6 alkyl. Embodiment 77: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein each R9 They are independently selected from the group consisting of H, methyl and ethyl. Embodiment 78: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R13 H. Embodiment 79: a compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein R13 Department C1 -C6 alkyl. Example 80: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R14 H. Example 81: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R13 H and R14 H. Example 82: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein m is 1, 2 or 3 and n is 1, 2 3 or 4. Embodiment 83: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk), wherein m is 1, 2 or 3. Embodiment 84: A compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein n is 1, 2, 3 or 4. Example 85: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )n R6 , -NH(CH2 )n C(=O)R6 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CHR9 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NH(CH2 )m C(=O)N(R5 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR5 -NHR8 , -NH (CHR9 )n OR9 -NHCH2 (C(R9 )2 )n OR9 , 8-oxa-3-azabicyclo[3.2.1]octyl,Or with independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Group substitution; each R5 Independently selected from C1 -C6 Alkyl and -(CH2 )n OR9 ; R6 An unsubstituted 4 to 6 membered heterocycloalkyl or C having 1 to 2 ring members independently selected from N, NH and O3 -C6 Cycloalkyl; each R7 Independently selected from C1 -C6 Alkyl, hydroxy and pendant oxy; each R8 Independently selected from C1 -C6 Haloalkyl and -(C(R9 )2 )n OR9 ; each R9 Lines are independently selected from H and C1 -C6 Alkyl; R16 Department C1 -C6 Alkyl; m series 1, 2, 3, 4, 5 or 6 and n series 1, 2, 3, 4, 5 or 6. Example 86: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 -NHR8 , 8-oxa-3-azabicyclo[3.2.1]octyl,Or with independently selected from N, NH, NR16 Or 4 to 6 membered heterocycloalkyl groups of 1 to 2 ring members of O, which are unsubstituted or 1 to 2 R7 Group substitution; each R5 Independently selected from C1 -C6 Alkyl and -(CH2 )n OR9 ; R6 Is independently selected from N, NH, NR16 And 4 to 6 membered heterocycloalkyl or C of 1 to 2 ring members3 -C6 Cycloalkyl; each R7 Independently selected from C1 -C6 Alkyl, hydroxy and pendant oxy; each R8 Independently selected from C1 -C6 Alkyl, C1 -C6 Haloalkyl and -(C(R9 )2 )n OR9 ; each R9 Lines are independently selected from H and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 87: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n R6 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 , -NH (CHR9 )n C(=O)R6 -NHR6 -NH2 , -N(R5 )2 Or -NHR8 ; each R5 Independently selected from C1 -C6 Alkyl and -(CH2 )n OR9 ; R6 Is independently selected from N, NH, NR16 And unsubstituted 4 to 6 membered heterocycloalkyl or C of 1 to 2 ring members of O3 -C6 Cycloalkyl; each R8 Independently selected from C1 -C6 Alkyl, C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 88: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)(CH2 )m N(R5 )2 , -NHC(=O)(CH2 )m NHR5 , -NHC(=O)(CH2 )m NH2 , -NHC(=O)(CHR9 )n NHR8 , -NH (CHR9 )n C(=O)N(R8 )2 -NH2 , -N(R5 )2 Or -NHR8 ; each R5 Independently selected from C1 -C6 Alkyl and -(CH2 )n OR9 ; each R8 Independently selected from C1 -C6 Alkyl, C1 -C6 Haloalkyl, -(C(R9 )2 )n OR9 And substituted by 1 to 3 -OH1 -C6 Alkyl; each R9 Lines are independently selected from H and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 89: a compound of the formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein R1 Department-NHC(=O)R6 , -NHC(=O)(CHR9 )n R6 , -NH (CHR9 )n C(=O)R6 Or -NHR6 ; R6 Is independently selected from N, NH, NR16 And unsubstituted 4 to 6 membered heterocycloalkyl or C of 1 to 2 ring members of O3 -C6 Cycloalkyl; each R9 Lines are independently selected from H and C1 -C6 An alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. Example 90: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk), wherein L system-CH2 -; Y1 Department-CH2 CH2 -; Y2 Department-CH2 CH2 -; Y3 Department-XCH2 -; X-CH2 -; R1 Department-NHC(=O)R6 ; R2 Department C1 -C6 Alkyl; R3 Department C1 -C6 Alkyl; R4 Department C1 -C6 Alkyl; R6 An unsubstituted 4 to 6 membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH and O; R13 H; R14 H; and each R17 H. Embodiment 91: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 4-((5) -(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7 -tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)oxetane-3-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(dimethylamino)acetamide; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazol[ 3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Double loop [2. 2. 2] oct-1-yl)morpholine-3-carboxamide; (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-3-carboxamide; 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4, 3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-oxa-6-azaspiro[3. 3] heptane; 4-(1-((4-aminobicyclo)[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl-1H-pyrazole And [3,4-d]pyrimidin-6-amine; 4-(2-((4-aminobicyclo)[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl-1H-pyrazole And [3,4-d]pyrimidin-6-amine; 4-(1-((4-aminobicyclo)[2. 2. 2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-amine; 4-(2-((4-aminobicyclo)[2. 2. 2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-amine; 4-((5-(5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine-7 -yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 1,6-dimethyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[3,4 -d]pyrimidine; 1,3,5-trimethyl-7-(3-methyl-1-((4-(pyrrolidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[4,3 -d]pyrimidine; N-(2-methoxyethyl)-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d Pyrimidine-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-amine; 4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine; 2-(ethylamino)-N-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d] Pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) acetamidine; 4-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine; 2-(ethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[ 4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) acetamidine; 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine-7- -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(oxetan-3-ylmethyl) ) double loop [2. 2. 2] oct-1-amine; 3-(dimethylamino)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4] , 3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2]oct-1-yl)propanamine; 4-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine) -7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine; 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; N-cyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine- 7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; N,N-dicyclobutyl-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d] Pyrimidine-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 6-methyl-4-(3-methyl-1-((4-(piperidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[3,4 -d]pyrimidine; 6-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[3,4 -d]pyrimidine; (3-((4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)amino)methyl)oxetan-3-yl)methanol; N-(4-((3-methyl-5-(1,3,5-trimethyl) -1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Base) double ring [2. 2. 2] oct-1-yl)azetidin-3-carboxamide; (S)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H) -pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Double loop [2. 2. 2] oct-1-yl)morpholine-3-carboxamide; (S)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazole) And [4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)morpholine-2-carboxamide; (R)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazole) And [4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)morpholine-3-carboxamide; (R)-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazole) And [4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)morpholine-2-carboxamide; 3,6-dimethyl-4-(3-methyl-1-((4-morpholinylbicyclo)[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)isoxazo[5,4-d Pyrimidine; 1,3,5-trimethyl-7-(3-methyl-1-((4-(piperidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[4,3 -d]pyrimidine; 1,6-dimethyl-4-(3-methyl-1-((4-(piperidin-1-yl))bicyclo[2. 2. 2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[3,4 -d]pyrimidine; 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(trimethylene)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro- 2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 1]hept-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-ol; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)methanesulfonamide; (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-yl) tert-butyl (meth)aminecarboxylate; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2. 2. 2] oct-1-amine; (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) carbamic acid 1-methylcyclopropyl ester; 3-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) )-3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[1. 1. 1] pent-1-amine; 4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-amine; N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropylbicyclo[2. 2. 2] oct-1-amine; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)amino)propan-1-ol; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) -3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethylbicyclo[2. 2. 2] oct-1-amine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-( Pyrrolidin-1-yl)bicyclo[2. 2. 2] oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-(4-((5-(1,6) -Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-di Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; N-(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; -((3-methyl-5-(2-methylquinolin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 1-((4-(azetidin-1-yl)bicyclo[2. 2. 2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine 4-yl)-7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 1,1-di-dioxide 4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)thiomorpholine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-( (4-(piperidin-1-yl)bicyclo[2. 2. 2] oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 1-(4-((5-(1,6) -Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)azetidin-3-ol; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl ) double loop [2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-methoxyethyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-ethoxyethyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-ethoxyethyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylbicyclo[2. 2. 2] oct-1-amine; (3S,4R)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)pyrrolidine-3,4-diol; (S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)pyrrolidin-3-ol; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)amino)-N,N-dimethylacetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4] -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)-N-methyloxetan-3-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-isopropyl -N-methylbicyclo[2. 2. 2] Oct-1-amine; N-cyclobutyl-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2. 2. 2] oct-1-amine; (3S, 4S)-1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)pyrrolidine-3,4-diol; 1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2. 2. 2] oct-4-amine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-( Pyrrolidin-1-yl)-2-oxabicyclo[2. 2. 2]oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(6-(4-fluoro) Phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-(4-(1-(4-aminobicyclo)[2. 2. 2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)pyridin-2-yl Benzonitrile; 3-methyl-5-(2-phenylpyridin-4-yl)-1-((4-(pyrrolidin-1-yl)bicyclo[2. 2. 2] oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 2-methyl-4-(3-methyl- 1-((4-(pyrrolidin-1-yl)bicyclo[2. 2. 2] oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1,7-naphthyridine; 4- ((5-(2-(4-Fluorophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(2-(2-fluoro-4-methylphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(2-(4-methoxyphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(2-(p-tolyl)pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-amine; 4-(2-(5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)ethyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(2,8-dimethyl-1,7-naphthyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((3-methyl-5-(2-methyl-6-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyridyl Zoxao[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-([2,2'-bipyridyl)-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-( Piperidin-1-yl)-2-oxabicyclo[2. 2. 2]oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(1,6-dimethyl) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)-N-(1-methoxypropan-2-yl)bicyclo[2. 2. 2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethyl-N-methylbicyclo[2. 2. 2] oct-1-amine; 1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethyl-2-oxabicyclo[2. 2. 2] oct-4-amine; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)amino)-1-(piperidin-1-yl)ethanone; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2. 2. 2] oct-1-yl)-2-(pyrrolidin-1-yl)acetamide; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2- Methoxy-2-methylpropyl)bicyclo[2. 2. 2] oct-1-amine; 1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-2-oxabicyclo[2. 2. 2] oct-4-amine; 4-((5-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; 4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-1-methylpiperazin-2-one; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-3-(dimethylamino)propanamide; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4] -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)amino)-1-(pyrrolidin-1-yl)ethanone; (R)-4-(4-((5-(1,6-dimethyl-1H-py) Zoxao[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Methyl)bicyclo[2. 2. 2] oct-1-yl)-2-methylmorpholine; 1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-4-methylpiperazin-2-one; (S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3, 4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2. 2. 2] oct-1-yl)-2-methylmorpholine; (2S,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2,6-dimethylmorpholine; (2S,6S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2. 2. 2] oct-1-yl)-2,6-dimethylmorpholine; N-(cyclobutylmethyl)-1-((5-(1,6-dimethyl-1H-pyrazolo[3, 4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2 -oxabicyclo[2. 2. 2] oct-4-amine; (2R,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2,6-dimethylmorpholine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine) 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(ethylamino)acetamide; 3-amino-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2. 2. 2] oct-1-yl)propanamine; 6-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-oxa-6-azaspiro[3. 3] heptane; (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(methylamino)propanamide; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3, 4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2. 2. 2] oct-1-yl)-2-(methylamino)propanamide; 1-((4-(1H-imidazol-1-yl)bicyclo[2. 2. 2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; (1R,5S)-3-(4-((5-(1,6-dimethyl-1H-pyrazole) And [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Base) double ring [2. 2. 2] oct-1-yl)-8-oxa-3-azabicyclo[3. 2. 1]octane; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(methylamino)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-4-methylmorpholine-3-carboxamide; 1-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4] -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2 . 2. 2] oct-1-yl)amino)-2-methylpropan-2-ol; 2-(ethylamino)-N-(4-((3-methyl-5-(5-methyl-)- 1H-pyrazolo[4,3-b]pyridin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl ) double loop [2. 2. 2] oct-1-yl)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-2-carboxamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4) -yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-3-(ethylamino)propanamide; N-ethyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; (S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-3-methylmorpholine; (R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-3-methylmorpholine; N-(2-methoxyethyl)-4-((3-methyl-5-(2-phenylpyridin-4-yl)) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)azetidin-3-carboxamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(ethyl(methyl)amino)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2. 2. 2] oct-1-yl)-2-(3-fluoroazetidin-1-yl)acetamide; 2-(bis(trimethylenemethyl)amino)-N-(4-(( 5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-hydroxyacetamidine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(3-hydroxyazetidin-1-yl)acetamide; (3-((4-((5-(1,6-dimethyl-) 1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1 -yl)methyl)bicyclo[2. 2. 2] oct-1-yl)amino)methyl)oxetan-3-yl)methanol; N-(4-((5-(1,6-dimethyl-1H-pyrazol[ 3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Double loop [2. 2. 2] oct-1-yl)-2-(N-methylmethylsulfonylamino)acetamide; N-(4-((5-(1,6-dimethyl-1H-pyrazole) [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl ) double loop [2. 2. 2] oct-1-yl)-2-(N-methylacetamido)acetamide; 4-((3-methyl-5-(6-methyl-1-(trimethyl)methyl) -1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Base) double ring [2. 2. 2] oct-1-amine; (S)-N-(4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-3-carboxamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4) -yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-3-(methylamino)propanamide; N-cyclobutyl-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4] -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2- Oxybicyclo[2. 2. 2] oct-4-amine; N-cyclobutyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-amine; (4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) carboxylic acid tert-butyl ester; (4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) carbamic acid tert-butyl ester; (4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6) ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl) carboxylic acid tert-butyl ester; (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 1] hept-1-yl) carbamic acid tert-butyl ester; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3 -Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-amine, and 4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] Oct-1-amine. Embodiment 92: A compound of the formula (A), the formula (I), the formula (II), the formula (Ia to Ip) and the formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, selected from the group consisting of: N-(4- ((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)oxetane-3-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(dimethylamino)acetamide; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazol[ 3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Double loop [2. 2. 2] oct-1-yl)morpholine-3-carboxamide; (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-3-carboxamide, and 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4] , 3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-oxa-6-azaspiro[3. 3] Heptane. Depending on the choice of starting materials and processes, certain embodiments of the compounds of the invention exist in the form of any of the possible isomers or as a mixture thereof, for example as a pure optical isomer or as a A mixture of structures, such as a racemate and a mixture of diastereomers, is present, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. The optically active (R)- and (S)-isomers can be prepared using a palmitic synthon or a palmitic reagent or using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration. All tautomeric forms are intended to be included in the present invention. In certain embodiments, the compounds of formula (A), formula (I), formula (II), formula (Ia to Ip), and formula (IIa to IIk) are by formula (A), formula (I), The free base form of the compound of formula (II), formula (Ia to Ip) or formula (IIa to IIk) is reacted with a stoichiometric amount of a suitable pharmaceutically acceptable organic or inorganic acid or a suitable anion exchange reagent to prepare a medicament An acceptable acid addition salt. Certain compounds of the invention may form acid addition salts by the presence of an amine group or a group similar thereto. Alternatively, the salt forms of the compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk) are prepared using salts of the starting materials or intermediates. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Organic or inorganic acids used to form certain pharmaceutically acceptable acid addition salts of compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk) Including, but not limited to, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, citric acid, leaf green tea acid, citric acid, ethanedisulfonic acid, fumaric acid, D -glyceryl-D-gulonic acid, galactosedioic acid, galactosedioic acid/mucosic acid, gluceptic acid, glucoheptonoic acid, gluconic acid, glucuronic acid , glutamic acid, glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfate, malic acid, maleic acid, propylene Acid, mandelic acid, mesylic acid, methanesulfonic acid, mucic acid, naphthoic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid , nitric acid, octadecanoic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, polygalacturonic acid, propionic acid, sebacic acid, stearic acid, succinic acid, sulfosalicylic acid, sulfuric acid, wine Stone acid, p-toluenesulfonic acid, trifluoroacetic acid and triphenylacetic acid. A list of additional suitable acid addition salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa. (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002. Salts of the compounds of the present invention may be obtained by using a suitable base Conversion of a reagent to a free compound. Pharmaceutically acceptable acid addition salts of the compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk) include (but Not limited to) acetate, adipate, ascorbate, aspartate, benzoate, besylatye, benzenesulfonate, bicarbonate/carbonate, hydrogen sulfate Salt/sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride, leaf green tea, citrate, ethanedisulfonate Edisylate), ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, pentane Diacid salt, glycolate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate Lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalene Napsylate, 2-naphthalenesulfonate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, octadecanoate, oleate, oxalic acid Salt, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, galacturonate, propionate, sebacate, stearate, succinate , sulfosalicylic acid salt, sulfate, tartrate, toluenesulfonate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate and xinafoate salt form. In an embodiment, the invention provides N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4) ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)oxetane-3-amine, which is acetate, adipate, ascorbate, aspartate, benzoate, benzenesulfonate, benzenesulfonic acid Salt, bicarbonate/carbonate, hydrogen sulfate/sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride, chlorophylline Salt, citrate, ethanedisulfonate, ethanedisulfonate, fumarate, glucoheptonate, glucoheptonate, gluconate, glucuronate, glutamate, pentane Diacid salt, glycolate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate , malonate, mandelate, methanesulfonate, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, 2-naphthalenesulfonate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, Galacturonate, propionate, sebacate Stearate, succinate, sulfosalicylic acid, sulfate, tartrate, tosylate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate or sulphate Salt form. In one embodiment, the invention provides N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) 4-,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-(dimethylamino)acetamide, which is acetate, adipate, ascorbate, aspartate, benzoate, besylate , benzenesulfonate, bicarbonate/carbonate, hydrogen sulfate/sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride , chlorophylline, citrate, ethanedisulfonate, ethanedisulfonate, fumarate, glucoheptonate, glucoheptonate, gluconate, glucuronate, glutamine Acid salt, glutaric acid salt, glycolate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, cis. Oleate, malonate, mandelate, methanesulfonate, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, 2-naphthalenesulfonate, naphthalene Sulfonate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/phosphoric acid Dihydrogen salt, galacturonate, propionate, bismuth Acid salt, stearate, succinate, sulfosalicyrate, sulfate, tartrate, tosylate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate Or in the form of a naphthenate salt. In one embodiment, the invention provides (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-3-carboxamide, which is acetate, adipate, ascorbate, aspartate, benzoate, benzenesulfonate, besylate , bicarbonate/carbonate, hydrogen sulfate/sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride, chlorophylline , citrate, ethanedisulfonate, ethanedisulfonate, fumarate, glucoheptonate, glucoheptonate, gluconate, glucuronate, glutamate, glutaric acid Acid salt, glycolate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, Malonate, mandelate, methanesulfonate, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, 2-naphthalenesulfonate, naphthalenesulfonate, 2 -naphthalene sulfonate, nicotinic acid salt, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, half Lactose, propionate, sebacate, Fatty acid, succinate, sulfosalicylic acid salt, sulfate, tartrate, toluenesulfonate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate or xanthate Salt salt form. In one embodiment, the invention provides (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)morpholine-3-carboxamide, which is acetate, adipate, ascorbate, aspartate, benzoate, benzenesulfonate, besylate , bicarbonate/carbonate, hydrogen sulfate/sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride, chlorophylline , citrate, ethanedisulfonate, ethanedisulfonate, fumarate, glucoheptonate, glucoheptonate, gluconate, glucuronate, glutamate, glutaric acid Acid salt, glycolate, horse urate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, Malonate, mandelate, methanesulfonate, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, 2-naphthalenesulfonate, naphthalenesulfonate, 2 -naphthalene sulfonate, nicotinic acid salt, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, half Lactose, propionate, sebacate, Fatty acid, succinate, sulfosalicylic acid salt, sulfate, tartrate, toluenesulfonate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate or xanthate Salt salt form. In one embodiment, the invention provides 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7) -yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2. 2. 2] oct-1-yl)-2-oxa-6-azaspiro[3. 3] heptane, which is acetate, adipate, ascorbate, aspartate, benzoate, besylate, besylate, bicarbonate/carbonate, hydrogen sulfate/ Sulfate, bromide/hydrobromide, camphorsulfonate, dextrocamphor, citrate, chloride/hydrochloride, chlorophylline, citrate, ethanedisulfonate, B Disulfonate, fumarate, glucoheptonate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, Hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonic acid Salt, methanesulfonate, methyl sulfate, mucate, naphthoate, naphthalenesulfonate, 2-naphthalenesulfonate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitric acid Salt, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, galacturonate, propionate, azelaic acid Salt, stearate, succinic acid Salt, sulfosalicylic acid salt, sulfate, tartrate, toluenesulfonate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenyl acetate or xinafoate salt. Any formula given herein is also intended to indicate the unlabeled form of the compound and the isotopically labeled form. An isotopically-labeled compound has a structure depicted by the formula given herein, except that one or more atomic systems are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as respectively2 H,3 H,11 C,13 C,14 C,15 N,18 F31 P,32 P,35 S,36 Cl,123 I,124 I,125 I. The invention includes various isotopically labeled compounds as defined herein, for example, wherein such radioisotopes are present3 H and14 C or any of them have non-radioactive isotopes such as2 H and13 C. These isotopically labeled compounds are suitable for metabolic studies (using14 C), reaction kinetics study (using, for example2 H or3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), which include drug or matrix distribution analysis, or radiotherapy for patients . In particular,18 F or labeled compounds may be particularly useful for PET or SPECT studies. Isotopically labeled compounds of formula (I) can be prepared, usually by conventional techniques known to those skilled in the art, or by methods analogous to those described in their accompanying examples and preparations, using appropriate isotopically labeled reagents. It was previously prepared without an isotope-labeled reagent. In addition, with heavier isotopes (specifically (ie,2 H or D)) substitutions may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements or therapeutic index improvements. It is to be understood that in the present context, hydrazine is regarded as a substituent of the compound of the formula (I). The concentration of this heavier isotope (specifically, helium) can be defined by the isotope concentration factor. As used herein, the term "isotopic concentration factor" means the ratio between the isotope abundance of a given isotope and the natural abundance of a given isotope. If a substituent in a compound of the invention is indicated as hydrazine, the compound has the following isotope concentration factor for each of the specified hydrazine atoms: at least 3500 (incorporating 52.5% hydrazine under each specified argon atom), at least 4000 (and 60%氘), at least 4500 (incorporated with 67.5%氘), at least 5000 (incorporated 75%氘), at least 5500 (incorporated 82.5%氘), at least 6000 (incorporated 90%氘), at least 6333.3 (and 95% 氘), at least 6466.7 (incorporated 97% 氘), at least 6600 (incorporated 99% 氘) or at least 6633.3 (incorporated 99.5% 氘). The pharmaceutically acceptable solvates according to the invention include those in which the solvent for crystallization can be substituted by an isotope, for example, D2 O, d6 - acetone, d6 - DMSO. A compound of the invention containing a group which can serve as a donor and/or acceptor for hydrogen bonding can form a co-crystal with a suitable eutectic former. Such co-crystals can be prepared from the compounds of the invention by known eutectic formation processes. Such processes include crystallization, heating, co-sublimation, co-melting or contacting and separating the eutectic formed by the compound of the present invention and the eutectic former in a solution. Suitable eutectic formers include those described in their WO 2004/078163. Accordingly, the present invention further provides cocrystals comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) and formula (IIa to IIk). All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted. The use of any and all examples or illustrative language (such as "such as") is intended to be illustrative of the invention. Any asymmetric atom of the compound of the invention (e.g., carbon or the like) may exist as a racemic or enantiomerically enriched form, for example, (R )-, (S )-or(R ,S ) - Configuration. In some embodiments, each asymmetric atom is at (R )-or(S - a configuration having at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% An astigmatism excess or at least 99% enantiomeric excess. Substituents at the atom having an unsaturated double bond may, if possible, be cis-(Z )- or trans-(E ) - Form exists. Thus, as used herein, a compound of the invention may exist in any of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, substantially pure Geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof. Any resulting mixture of isomers may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemics based on physicochemical differences of the components, for example by chromatography and/or fractional crystallization. Things. Any resulting racemate of the final product or intermediate can be resolved to the optical enantiomer by known methods, for example, by isolating its diastereomeric salt with an optically active acid or base and releasing optical activity. Acidic or basic compound. In particular, the basic moiety can thus be used to resolve a compound of the invention to its iso-enantiomer, for example, by fractional crystallization with an optically active acid (eg, tartaric acid, benzotrityl tartaric acid, diethyl hydrazine) a salt formed from tartaric acid, di-O, O'-p-tolylcarbyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by palm chromatography, for example, using high pressure liquid chromatography (HPLC) with a palmitic adsorbent. Further, the compound of the present invention (including its isocratic salt) may also be obtained in the form of its hydrate or other solvent for its crystallization. The compounds of the present invention may be inherently or by design and form solvates with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to include both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the invention, including a pharmaceutically acceptable salt thereof, with one or more solvent molecules. These solvent molecules are commonly used in the pharmaceutical field as solvent molecules known to be harmless to the recipient, for example, water, ethanol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. The compounds of the invention, including their salts, hydrates and solvates, may be formed intrinsic or by design to form polymorphs.For manufacturing (A) Method of its sub-compound Described herein are general processes for the preparation of compounds of formula (A), formula (I), formula (II), formula (Ia to Ip), and formula (IIa to IIk). In the reactions described herein, reactive functional groups (eg, hydroxyl, amine, imido, thio or carboxy, wherein such are desired in the final product) can be protected from such reactions. The participation required by China and Africa. Within the scope of the present text, unless otherwise expressly indicated in the context, only groups that are not readily removable from the particular desired end product of the compound of the invention are designated as "protecting groups." The functional groups are protected by such protecting groups, protecting the basic body and its cleavage reaction systems, for example, in standard reference works such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999, "The Peptides"; Volume 3 (Editor: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, "Aminosäuren , Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982 and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag , Stuttgart 1974. The protecting group is characterized in that it can be easily removed (ie, no undesirable side reactions occur), for example, by solvolysis, reduction, photolysis, or under physiological conditions (eg, by enzymatic cleavage). except. Compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) are prepared by the methods described herein and as illustrated in the Examples. Non-limiting examples of synthetic schemes for making the compounds of the invention are set forth in Schemes 1 and 2. Scheme 1 illustrates an example of the manufacture of compounds of formula (A), formula (I) and formula (II) using Buchwald-Hartwig Amination, wherein Pd catalyzes the protected amine Crosslinking of an intermediate (Int-A) or a protected amine intermediate (Int-B) with a heteroaryl halide intermediate (Int-1) followed by deprotection to yield formula (Ia) or formula (IIa), respectively Compound, where R1 NH2 . Furthermore, alkylation or deuteration results in a compound of formula (Ia) or formula (IIa) wherein R1 It is further defined as herein. Option 1: Buchwald-Hartwig aminationIn additional embodiments, compounds of formula (A), formula (I), and formula (II) may be prepared by using the intermediates Int-2, Int-3, Int-4, Int-5, Int-6, Int- 7. Int-8, Int-9, Int-10 or Int-11 replacement intermediate (Int-1) is obtained, respectively obtaining the formula (Ic), the formula (Ib), the formula (If), the formula (Ig), and the formula (Id), Formula (Ie), Formula (Ij), Formula (Ii), Formula (Ik), Formula (Ih), Formula (IIc), Formula (IIb), Formula (IIf), Formula (IIg), Formula (IId), a compound of the formula (IIe), the formula (IIj), the formula (IIi), the formula (IIk) and the formula (IIh). Table 1 shows alternative intermediates and individual products, of which TGA system, TGB system,X1 Br, Cl, I or -SO3 CF3 , and Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 , R13 And R14 Is as defined herein. Table 1 The Pd catalyst used in the coupling reaction of Scheme 1 is selected from the group consisting of Pd(II) catalysts, for example, bis(tri-o-tolylphosphine)palladium(II) chloride, bis(tri-o-tolylphosphine) Pd ( Dba)2 , bis(tri-o-tolylphosphine) Pd2 (dba)3 PdCl2 (dppf), (tri-o-tolylphosphine) Pd(OAc)2 , Pd(OAc)2 And palladium rings. The desired system of Scheme 1 is selected from the group consisting of diphenylphosphinobinaphthalene (BINAP), diphenylphosphinoferrocene (DPPF), and tri-o-tolylphosphine (P(o-tol)).3 ), triphenylphosphine (PPh)3 ), tri-tert-butylphosphine (P(t-Bu)3 , 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl (BrettPhos), 2-(di- Tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (t-BuBrettPhos), 2-dicyclohexylphosphine Base-2',4',6'-triisopropylbiphenyl (XPhos), 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl (t- BuXPhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos) , 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos), 2'-(di-tert-butylphosphino)-N,N-dimethyl Biphenylene-2-amine, 2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl (t-BuDavePhos), 2-diphenylphosphino-2 ',6'-bis(dimethylamino)-1,1'-biphenyl (PhCPhos), 2-di(t-butyl)phosphino-2',4',6'-triisopropyl 3-methoxy-6-methylbiphenyl (RockPhos), 2-(di-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy 1,1'-biphenyl (AdBrettPhos), di-t-butyl (2',4',6'-tricyclohexyl-3,6-dimethoxy-[1,1'-biphenyl ]-2-yl) phosphine, di-tert-butyl (2',4',6'-triisopropyl-3,4,5,6-tetramethyl -[1,1'-biphenyl]-2-yl)phosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), 2-(2-di Cyclohexylphosphinoalkylphenyl)-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine (CPhos), 2'-(diphenylphosphino)-N,N'-di Methyl-(1,1'-biphenyl)-2-amine (PhDavePhos), 2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy -2',4',6'-triisopropyl-1,1'-biphenyl (JackiePhos), (2-biphenyl) di-t-butylphosphine (JohnPhos), (2-biphenyl) -Dicyclohexylphosphine (CyJohnPhos), 2-dicyclohexylphosphino-2'-methylbiphenyl (MePhos), 2-di-t-butylphosphino-2'-methyl)-1,1' -biphenyl (t-BuMePhos), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos), 2'-dicyclohexylphosphino-2,6-dimethoxy -1,1'-biphenyl-3-sulfonate sodium hydrate (sSPhos), racemic-2-(di-tert-butylphosphino)-1,1'-binaphthyl (TrixiePhos), 2- Di-t-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropylbiphenyl (Me4 t-BuXPhos), 2'-dicyclohexylphosphino-2,6-di-isopropyl-4-sulfonate-1,1'-biphenyl hydrate sodium salt (XPhos-SO3 Na), di-t-butyl (2',4',6'-triisopropyl-4,5-dimethoxy-3,6-dimethyl-[1,1'-biphenyl] -2-yl)phosphine and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[1,1'-biphenyl]-4-amine and tricyclohexylphosphine (P(Cy)3 ). The bases used in the coupling reactions of Scheme 1 include KOAc, NaOAc, K2 CO3 Na2 CO3 , NaOEt, KOtBu, NaOtBu, LiHMDS, Cs2 CO3 , K3 PO4 , NaOH, KOH, tBuOH and NEt3 . These coupling reactions are carried out at a temperature in the range of about 100 to 180 ° C or in a microwave oven. Further, a solvent such as benzene, toluene, 1,2-dimethoxyethane, acetonitrile, DCM, DMF, THF, dioxane, and N-methyl-2-pyrrolidone is used. The reaction can be carried out under an inert gas such as nitrogen or argon. Scheme 2 illustrates another embodiment for the manufacture of compounds of formula (A), formula (I) and formula (II) using a base catalyzed protected amine intermediate (Int-A) or a protected amine intermediate ( Crosslinking of Int-B) with a heteroaryl halide intermediate (Int-1) followed by deprotection to yield a compound of formula (Ia) or formula (IIa), respectively.1 NH2 . Further alkylation or deuteration results in a compound of formula (Ia) or formula (IIa) wherein R1 It is further defined as herein. Scheme 2: base-catalyzed cross-linkingIn additional embodiments, compounds of formula (A), formula (I), and formula (II) may be prepared by using the intermediates Int-2, Int-3, Int-4, Int-5, Int-6, Int- 7. Int-8, Int-9, Int-10 or Int-11 replacement intermediate (Int-1) is obtained, respectively obtaining the formula (Ic), the formula (Ib), the formula (If), the formula (Ig), and the formula (Id), Formula (Ie), Formula (Ij), Formula (Ii), Formula (Ik), Formula (Ih), Formula (IIc), Formula (IIb), Formula (IIf), Formula (IIg), Formula (IId), a compound of the formula (IIe), the formula (IIj), the formula (IIi), the formula (IIk) and the formula (IIh). Table 2 shows alternative intermediates and individual products, of which TGA system, TGB system,X1 Br, Cl, I or -SO3 CF3 , and Y1 , Y2 , Y3 , L, R1 , R2 , R3 , R4 , R13 And R14 Is as defined herein. Table 2 The bases used in the coupling reactions of Scheme 2 include DIPEA, Cs2 CO3 1,8-diazabicycloundec-7-ene (DBU), NEt3 , K2 CO3 CaCO3 Na2 CO3 , K3 PO4 , KF, KOAc, NaOEt, KOtBu and NaOH. These coupling reactions are carried out at a temperature in the range of about 80 to 180 ° C or in a microwave oven. Solvents for use in such coupling reactions of Schemes (VII) and (VIII) include H2 O, 2-methyl-THF, 2-methyl-THF/H2 O (1:1), THF, MeOH, butanol, tert-butanol, EtOAc, CAN, ACN, DMSO, NMP, toluene dimethylacetamide and DMF. The reaction can be carried out under an inert gas such as nitrogen or argon.Intermediate Int-A and Int-B Scheme 3 illustrates an embodiment for making intermediates Int-A and Int-B. Option 3. Scheme 4 illustrates an embodiment for making intermediates Int-A and Int-B. Option 4. The amine protecting group (Prot) in Schemes 1 to 4 is selected from the group consisting of methyl carbamate, 9-fluorenylmethyl formate (Fmoc), 2,2,2-trichloroethylamine (Troc), and amine formic acid. Third butyl ester (Boc), 2-(trimethyldecyl)ethyl carbamate (Teoc), allyl urethane (Alloc), benzyl carbamate (Cbz), benzylideneamine, p-toluene Indoleamine, trifluoroacetamide, acetamide, phthalimide, benzylamine, 4-methoxybenzylamine (PMB), allylamine and tribumeamine. The invention further encompasses any variant of the process of the invention wherein the intermediate product obtainable at any stage thereof is used as a starting material and the remaining steps are carried out, or wherein the starting material is formed on the spot under the reaction conditions, or The reaction components are used in the form of their isocratic or optically pure materials. The compounds and intermediates of the invention may also be converted into each other according to methods generally known to those skilled in the art. EXAMPLES The compounds of the invention can be produced as shown in the following examples. The following examples are intended to illustrate the invention and are not to be construed as limiting the invention. The temperature is given in degrees Celsius. If not mentioned otherwise, all evaporation is carried out under reduced pressure (usually between about 15 mm Hg and 100 mm Hg (= 20-133 mbar)). The structure of the final product, intermediate, and starting materials is confirmed by standard analytical methods (eg, microanalysis and spectral characteristics (eg, MS, IR, NMR)). Abbreviations used herein are abbreviations commonly used in the art. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthetic methods known to those of ordinary skill in the art or can be as described herein. The organic synthesis method is produced.abbreviation: BH3 -DMS borane dimethyl sulfide brine concentrated sodium chloride solution CPME cyclopentyl methyl ether d double peak dd double bimodal DCM dichloromethane dimethyl dimethyl acetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl hydrazine DIPEA diisopropylethylamine ESI electrospray ionization ESIMS electrospray ionization mass spectrometry EtOAc ethyl acetate EtOH ethanol eq equivalent HPLC high pressure liquid chromatography hr hour hrs hour IPA isopropanol LC-MS or LC/MS liquid chromatography and mass spectrometry MeOH methanol MS mass spectrometry m multiplex state mg mg min min mL ml mm mm Mmol millimole m/z mass-to-charge ratio nm nm nm nanomolar NMR NMR RT retention time rt room temperature s singlet t triplet TFA trifluoroacetic acid THF tetrahydrofuran UV UV μm micronInstrument method LC-MS method Method 1: The instrument contained an Agilent LC/MS system with a 1200 sll HPLC pump and a 6100 series single quadrupole mass spectrometer with electrospray (ESI) ionization. The sample was injected at 60 ° C on a Waters Acquity® HSS T3 column C18 1.8 μm 2.1 x 50 mm. The gradient pump method uses a flow rate of 0.9 mL/min throughout the 2.25 minute run to mobile phase A: at H2 0.05% TFA in O, and mobile phase B: 0.035% TFA in acetonitrile, 10% B to 100% B in 1.36 minutes. Method 2: 3.5 MIN_10 TO100B: The instrument contained an Agilent LC/MS system with a 1200 sl HPLC pump and a 6100 series single quadrupole mass spectrometer with electrospray (ESI) ionization. The sample was injected at 60 ° C on a Waters Acquity® HSS T3 column C18 1.8 μm 2.1 x 50 mm. The gradient pump method uses a flow rate of 0.9 mL/min throughout the 2.25 minute run to mobile phase A: at H2 0.05% TFA in O, and mobile phase B: 0.035% TFA in acetonitrile, 10% B to 100% B in 1.36 minutes.Tail base The tail group intermediates used to obtain the compounds of the present invention are shown below and in Table 4, and their respective syntheses are also described below. The synthesis of certain reagents used to obtain such intermediates is also described below unless purchased.Purchased reagent Synthesis of certain intermediates used in the synthesis of various tail groups Synthesis of 4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl 4-(trifluoromethyl)benzenesulfonate (i-B1)Step 1: To a solution of 4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid (4.565 g, 16.9 mmol) in THF (30 mL) Solution addition BH3 -DMS (5.15 mL, 3.0 eq.). After the addition, the reaction was further stirred overnight at room temperature. LC/MS indicated the completion of the reaction. The reaction was then treated with the dropwise addition of 10% citric acid. After aqueous workup, ISCO purification (hexanes / EtOAc) afforded (t-butyl) (4-(hydroxymethyl)bicyclo[2.2.2] oct-1-yl)carbamic acid as a white solid.1 H NMR (400 MHz, DMSO-d6) δ 6.31 (s, 1H), 4.31 (t, J = 5.4 Hz, 1H), 2.99 (d, J = 5.4 Hz, 2H), 1.75 - 1.61 (m, 6H) , 1.41 - 1.27 (m, 15H). ESIMS (M+H+ ) 256.20. Step 2: To a solution of (4-(hydroxymethyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (1.021 g, 4.0 mmol) and 4-(trifluoromethyl) at room temperature Add Et in a mixture of benzenesulfonium chloride (1.566 g, 6.4 mmol, 1.6 eq.) and DCM (10 mL)3 N (1.12 mL, 2.0 eq.) and DMAP (49 mg, 0.1 eq.). After the addition, the resulting mixture was further stirred at room temperature for 4 hours. LC/MS indicated the completion of the reaction: two major peaks, m/z 408 (M+H+ -56) The product peak and the intermediate peak of m/z 331. After aqueous workup, it was purified by EtOAc (hexane /EtOAc) to afford product (i-B1) as white solid.1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 6.39 (s, 1H), 3.74 (s, 2H), 1.75 - 1.57 (m, 6H), 1.42 - 1.26 (m, 15H). For Ctwenty one H28 F3 NO5 S, ESIMS calculated value (M+H+ 464.17, found 408.00 (M+H+-56). Synthesis of 4-(trifluoromethyl)benzenesulfonic acid (3-((t-butoxycarbonyl)amino)bicyclo[1.1.1]pent-1-yl)methyl ester (i-B2)Step 1: LiAlH at 0 ° C4 (83 mg, 2.188 mmol) was dissolved in THF (20 mL). The starting material 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-carboxylic acid methyl ester (240 mg, 0.995 mmol) was dissolved in 5 mL THF and then at 0 Add to LiAlH at °C4 Solution. After the reaction was completed, the reaction mixture was warmed to room temperature and stirred for 2 hr. Then add saturated Na2 SO4 The solution is used to quench the reaction. After filtration, the solvent was removed to obtain (3-(hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminecarboxylic acid tert-butyl ester for use in the next step. Step 2: (3-(Hydroxymethyl)bicyclo[1.1.1]pent-1-yl)aminecarboxylic acid tert-butyl ester (180 mg, 0.844 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (206 mg, 0.844 mmol) and DIPEA (0.295 mL, 1.688 mmol) were taken in DCM (5 mL) and the mixture was stirred at 25 ° C for 5 hours. After work-up and preparative LC-MS, 4-(trifluoromethyl)benzenesulfonic acid (3-((t-butoxycarbonyl)amino)bicyclo[1.1.1] for the next step was obtained. Pent-1-yl)methyl ester (i-B2). ESIMS (M+H+ ) 422.1. Synthesis of 2-(4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)ethyl methanesulfonate (i-B3)2-(4-((Tertibutoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)ethyl methanesulfonate (i-B3) by (287 mg, 1.065 mmol) (4-(2-Hydroxyethyl)bicyclo[2.2.2]oct-1-yl)carbamic acid tert-butyl ester and triethylamine (216 mg, 2.131 mmol) were combined in DCM (10.700 ml). To this solution was added methanesulfonate chloride (159 mg, 1.385 mmol) at 0 °C. After the addition, the resulting mixture was further stirred at 25 ° C for 18 hours. LC-MS indicated the completion of the reaction. After work up (addition of water and extraction in DCM), the organic layer was dried4 Dry over, filter and concentrate in vacuo. The residue was used without further purification. 1H NMR (400 MHz, chloroform-d) δ 4.23 (d, J = 6.0 Hz, 1H), 4.15 (t, J = 7.3 Hz, 2H), 2.92 (s, 3H), 1.78 - 1.71 (m, 6H) , 1.55 - 1.50 (m, 2H), 1.50 - 1.42 (m, 6H), 1.35 (s, 9H). ESIMS (M+H+ ) 348.2. Synthesis of 4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl (i-B4)Trifluoromethanesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl ester (i-B4) by following for 2-methanesulfonic acid Preparation of 4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)ethyl ester (i-B3), except for the use of 4-((t-butoxy) Methyl carbonyl)amino)bicyclo[2.2.1]heptane-1-carboxylic acid methyl ester replacement (4-(2-hydroxyethyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester . 4-((Tert-butoxycarbonyl)amino)bicyclo[2.2.1]heptan-1-yl)methyl trifluoromethanesulfonate (i-B4) is usually used as the crude product. Synthesis of 4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl methanesulfonate (i-B5)Methanesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl ester (i-B5) by following 2-(4) for methanesulfonic acid Preparation of -((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)ethyl ester (i-B3) by using (4-(2-hydroxyethyl)bicyclic [2.2.1] H-butyryl-carboxylic acid tert-butyl ester was replaced by (3-(2-hydroxyethyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester. Methanesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl ester (i-B5) is usually used as a crude product. 4-(Trifluoromethyl)benzenesulfonic acid (4-((t-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]oct-1-yl)methyl ester (i-B6) Synthesis4-(Trifluoromethyl)benzenesulfonic acid (4-((t-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]oct-1-yl)methyl ester (i-B6) By using 4-(trifluoromethyl)benzenesulfonic acid (3-((t-butoxycarbonyl)amino)bicyclo[1.1.1]pent-1-yl)methyl ester (i-B2) Prepared by a synthetic method, except that 4-((t-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylic acid methyl ester was used to replace 3-((Third Oxycarbonyl)amino)dicyclo[1.1.1]pentan-1-carboxylic acid methyl ester. RT (Method 1): 1.84 minutes. For C20 H26 F3 NO6 S (M+H+ ESIMS calc. 465.5, found 488.5 (M + Na).Synthesis of tail group (4-((4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amine T-butyl formate (TG1) and (4-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2. Synthesis of 2] oct-1-yl) carbamic acid tert-butyl ester (TG2)Step 1: 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (i-A0) (165 mg, 0.64 mmol) in methanol (13.5 ml) (2.91 ml, 16.66 mmol) was treated with benzyl chloroformate (0.837 ml, 5.95 mmol). The entire mixture was stirred for 18 hours. LCMS showed the reaction was complete and the reaction mixture was concentrated in vacuo. The residue was loaded onto a 24 g cartridge column and used in 10% methanol in DCM to provide 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5- Benzyl carboxylate (for C14 H15 N3 O2 (M+H+ ), MS calculated 258.1, measured value 258.1). Step 2: Add 4 to a 20 mL scintillation vial containing benzyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (165 mg, 0.641 mmol) 4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl (-trifluoromethyl)benzenesulfonate (i-B1) (446 mg, 0.962 mmol) , cesium carbonate (418 mg, 1.28 mmol) and anhydrous DMSO (3.2 mL). The mixture was heated to 110 ° C for 18 hours and then diluted in ethyl acetate and water. A citric acid solid was added to neutralize the pH. After stratification, the aqueous layer was back extracted three times with ethyl acetate. All organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a 40 g silica gel column using 0 to 10% methanol in DCM to provide a mixture of two desired res.20 H32 N4 O2 (M+H+ ), MS calculated 361.3, found 361.3). Step 3: To a mixture of (TG1a) and (TG2a) (102 mg, 0.21 mmol) was added palladium on carbon (0.0220 g, 0.0207 mmol) and ethanol (1 ml). The mixture was stirred with hydrogen (65 psi) for 18 hours; LCMS showed ~90% conversion. The mixture was filtered, washed with methanol and concentrated in vacuo. The residue was loaded onto a 40 g cartridge column using 0 to 80% isopropanol in DCM with 2% ammonia as the modifier to provide the crude product used directly in the separation step (below). Partial isomer separation 56 mg (0.16 mmol) from step 2 TG1 and TG2 using SFC chromatography on a 21 x 250 mm cyano column (phase: 3 μm 4.6 x 50 mm, cyano, solvent mixture: CO2 : 85%; 1/1 v/v IPA: MeOH + 10 mm NH4 OAc -15%; Preparation conditions: 80 g/min, 88/6/6 CO2 /IPA/MeOH + 10 mm NH4OAc, ~ 115 bar, 2 min stack injection, 5.25 minutes elution time) was separated to provide (4-((4,5,6,7-tetrahydro-1H-pyrazole[ 4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG1; peak 2, RT 2.1 min, for Ctwenty one H34 N4 O2 (M+H+), ESIMS calc. 361.3, found 361.3) and (4-((4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl) Methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG2; peak 1, RT 1.71 min. for C20 H32 N4 O2 (M+H+), ESIMS calc. (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]xin- 1-butyryl carboxylic acid tert-butyl ester (TG3) and (4-((3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2) Synthesis of 3-butyl (2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG4)Step 1: Suspension of 3-methyl-1H-pyrazolo[4,3-c]pyridine (i-A1) (2.66 g, 19.98 mmol) in DMSO (80 ml) with 4-(trifluoromethyl) Benzobenzenesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl ester (i-B1) (9.26 g, 19.98 mmol) and cesium carbonate ( 13.02 g, 40.0 mmol). The mixture was heated to 120 ° C for 18 hours to complete, then cooled to room temperature and diluted in ethyl acetate and water. After partitioning, the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on a 120 g silica gel column using 0 to 80% ethyl acetate in hexanes and EtOAc (EtOAc) 3-H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (product 1). The gradient was 100% ethyl acetate extended to elute by-product (4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2. 2] Octan-1-yl) carbamic acid tert-butyl ester (product 2). Product 1: RT (LCMS Method 1): 1.510 minutes (mass – M+1 - 371.2),1 H NMR (400 MHz, methanol-d4 ) δ 9.07 (s, 1H), 8.37 (d, J = 6.1 Hz, 1H), 7.60 (d, J = 6.2 Hz, 1H), 6.18 (width s, 1H), 4.17 (s, 2H), 2.71 ( s, 3H), 1.87 (dd, J = 10.0, 5.9 Hz, 6H), 1.66 (dd, J = 10.0, 5.9 Hz, 6H), 1.47 (s, 9H). For Ctwenty one H30 N4 O2 (M+H+), ESI. Product 2: RT (LCMS Method 1): 1.47 min. For Ctwenty one H30 N4 O2 (M+H+), ESI. Step 2: Hydrogenation of product 1 (4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl) The third butyl carbamate (product 1) (3.6267 g, 9.79 mmol) was hydrogenated using the H-cube system. Once completed, the reaction solution was concentrated and loaded onto a 120 g cartridge column for 0 to 100% IPA in DCM with 1% ammonia as the modifier and then extended to 100% IPA with 1% ammonia as the modifier. To dissolve (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2 ] oct-1-yl) carboxylic acid tert-butyl ester (TG3):1 H NMR (400 MHz, CD3 OD) δ 3.73 (s, 2H), 3.65 (s, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.65 (t, J = 5.9 Hz, 2H), 2.12 (s, 3H), 1.87 - 1.74 (m, 6H), 1.61 - 1.47 (m, 6H), 1.39 (s, 9H); for Ctwenty one H34 N4 O2 (M+H+), ESIMS calc. Step 2: Hydrogenation of product 2 (4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]oct-1-yl) The third butyl carbamate (1.011 g, 2.73 mmol) was hydrogenated using the H-cube system. Once completed, the reaction solution was concentrated and loaded onto a 24 g cartridge column for 0 to 100% IPA in DCM at 3% NH3 Used as a modifier to produce (4-((3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[ 2.2.2] Octyl-1-yl)carbamic acid tert-butyl ester (TG4).1 H NMR (400 MHz, methanol-d4) δ 4.89 (d, J = 1.4 Hz, 1H), 3.75 (m 4H), 3.09 (t, J = 5.9 Hz, 2H), 2.72 (m, 2H), 2.15 ( s, 3H), 1.79 (m, 6H), 1.54 (m, 6H), 1.40 (s, 9H). For Ctwenty one H34 N4 O2 (M+H+), ESIMS calc. (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptane- Synthesis of 1-butyl) dimethyl butyl carbamate (TG5)Step 1: 3-methyl-1H-pyrazolo[4,3-c]pyridine (i-A1) (133 mg, 1.0 mmol), methanesulfonic acid (4-((Third)) at 80 °C Oxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methyl ester (i-B5) (351 mg, 1.1 mmol) and Cs2 CO3 The mixture in DMSO (2 mL) was stirred overnight. LC-MS showed the reaction was completed. The reaction mixture was then cooled to room temperature and diluted with EtOAc / water. The layer is separated and the organic layer is in Na2 SO4 Dry on top and then concentrate. The crude product was added (solid loading) to a 40 g silica gel column and used to elute from 0 to 100% EtOAc in hexanes. The fractions were collected and concentrated to give the product 1, (4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]hept-1 -butyl) butyl methacrylate, and product 2, (4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.1 ?hept-1-yl)-tert-butyl carbamate. Step 2: Use H-Cube: 90 ° C, 20 bar H2 , 10% Pd/C, 1 mL/min flow rate 220 mg (0.617 mmol) (4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Conversion of the tert-butyl [2.2.1]hept-1-yl)aminecarboxylic acid to the desired product (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazole) [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-yl)carbamic acid tert-butyl ester (TG5). RT (LCMS Method 2) 1.92 minutes. For C20 H32 N4 O2 (M+H+ ), MS calculated 361.5, found 361.5. Note: Product 2 was not hydrogenated. 1-((4-((Tertidinoxycarbonyl))amino)bicyclo[2.2.2]oct-1-yl)methyl)-7,7-dimethyl-6,7-dihydro-1H -pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG6a) and 2-((4-((t-butoxycarbonyl))amino)bicyclo[2.2. 2] oct-1-yl)methyl)-7,7-dimethyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid third Synthesis of butyl ester (TG7a)7,7-Dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (iA3) (120 mg, 0.477 Ment), 4-(trifluoromethyl)benzenesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl ester (i-B1) (220 Mg, 0.477 mmol) and Cs2 CO3 (156 mg, 0.477 mmol) was mixed in DMA (10 mL) and stirred at 120 ° C for one hour. After treatment and preparative LC-MS, 1-((4-((t-butoxycarbonyl))amino)bicyclo[2.2.2]oct-1-yl)methyl)-7,7-dimethyl Benzyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG6a) and 2-((4-((3rd butoxide) Alkylcarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl)-7,7-dimethyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine -5(4H)-carboxylic acid tert-butyl ester TG7a). 4-((7,7-Dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] Synthesis of oct-1-amine (TG6)1-((4-((Tertidinoxycarbonyl))amino)bicyclo[2.2.2]oct-1-yl)methyl)-7,7-di in dioxane (4 N) Methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG6a) (70 mg, 0.143 mmol) and HCl (0.433 mL) The mixture was stirred in MeOH (1 mL) and stirred at 50 ° C for 5 hr. 4-((7,7-Dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) was obtained after treatment and preparative LC-MS Methyl)bicyclo[2.2.2]oct-1-amine (TG6). 4-((7,7-Dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2] Synthesis of oct-1-amine (TG7)2-((4-((Tertidinoxycarbonyl))amino)bicyclo[2.2.2]oct-1-yl)methyl)-7,7-di in dioxane (4 N) Methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG7a) (70 mg, 0.143 mmol) and HCl (0.433 mL) The mixture was stirred in MeOH (1 mL) and stirred at 50 ° C for 5 hr. 4-((7,7-Dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl) was obtained after treatment and preparative LC-MS Methyl)bicyclo[2.2.2]oct-1-amine (TG7). 4-((3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2 Synthesis of oct-1-amine (TG8)Step 1: 291 mg (1 mmol) of 3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate at 80 °C Tert-butyl acid (i-A7), 510 mg (1.1 mmol) methanesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.1]hept-1-yl)methylmethane a mixture of sulfo(4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl ester and cesium carbonate (652 mg, 2.0 mmol) in DMSO (5 mL) Stir overnight. After cooling to room temperature, the mixture was diluted with EtOAc / water. The layers were separated and the aqueous extracted with EtOAc. Combined organic layer in Na2 SO4 It was dried and then concentrated to give a crude product. The crude product was added (solid loading) to a 40 g silica gel column and used to elute from 0 to 50% EtOAc in hexanes. The fractions were collected and concentrated to give the desired product, 1-((4-((t-butoxycarbonyl)amino)bicyclo[2.2.2] oct-1-yl)methyl)-3-(trifluoro) Methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG8a) and traces of 2-((4-( (t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl)-3-(trifluoromethyl)-2,4,6,7-tetrahydro-5H-pyridyl Zirta[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (TG9a). TG8a:1H NMR (500 MHz, methylene chloride-d2) δ 4.51 - 4.46 (m, 2H), 4.36 (s, 1H), 3.84 (s, 2H), 3.65 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.9 Hz, 2H), 1.82 – 1.73 (m, 6H), 1.59 - 1.52 (m, 6H), 1.46 (s, 9H), 1.38 (s, 9H). MS (ES+): 529.4 (M+1)+. TG9a: Method 1 (RT: 2.07 min), MS (ES+): 529.4 (M+1)+. Step 2: To 66 mg (0.125 mmol) of 1-((4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl)-3-(trifluoromethyl) ,6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (TG8a) in dioxane/MeOH (0.5 mL/0.3 mL HCl (4 M solution in dioxane, 0.5 mL) was added to the solution. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and lyophilized to give the final product as 4-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (TG8). Method 1 (RT = 0.9 min), MS (ES+): 329.2 (M+1)+. Methyl (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] Synthesis of tert-butyl octyl-1-amino)carbamate (TG10)Step 1: At 0 ° C in N2 Downward 1.85 g (4.0 mmol) 4-(trifluoromethyl)benzenesulfonic acid (4-((t-butoxycarbonyl)amino)bicyclo[2.2.2]oct-1-yl)methyl ester (i -B1) 208 mg (5.2 mmol) of NaH was added to a solution in THF. The mixture was warmed to room temperature and stirred for 30 minutes, then cooled back to 0 ° C, then CH was added dropwise3 I (2.84 g, 20.0 mmol). The resulting mixture was slowly warmed to room temperature and stirred overnight. LC-MS showed the desired product but the reaction was not completed. Add additional NaH (1.0 equivalents) and CH3 I (5.0 eq.) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched at 0 ° C by dropwise addition of 2.0 mL of 2-propanol and then dropwise addition of 3.0 mL of cold water. The mixture was then partitioned between EtOAc and water. The layers were separated and the aqueous extracted with EtOAc. Combined organic layer in Na2 SO4 Dry on top and then concentrate. The crude product was added to an 80 g silica gel column and used to elute from 0 to 30% EtOAc in hexanes. The fractions were collected and concentrated to give 4-(trifluoromethyl)benzenesulfonic acid (4-((t-butoxycarbonyl)(methyl)amino)bicyclo[2.2.2]oct-1-yl) ester. RT: 3.1 minutes (method 2). 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 8.2 Hz, 2H), 3.73 (d, J = 1.9 Hz, 2H), 2.82 (s , 3H), 2.04 - 1.95 (m, 6H), 1.53 - 1.42 (m, 15H). Step 2: 133 mg (1.0 mmol) 3-methyl-1H-pyrazolo[4,3-c]pyridine, 525 mg (1.1 mmol) 4-(trifluoromethyl)benzenesulfonic acid at 80 °C (4-((Tertidinoxycarbonyl)(methyl)amino)bicyclo[2.2.2]oct-1-yl)methyl ester and 652 mg (2.0 mmol) Cs2 CO3 The mixture in DMSO was stirred overnight. After cooling to room temperature, the mixture was diluted with EtOAc / water. The layer is separated and the organic layer is in Na2 SO4 Dry on top and then concentrate. The crude product was added (solid loading) to a 40 g silica gel column and used to elute from 0 to 100% EtOAc in hexanes. The fractions were collected and concentrated to give methyl (4-((3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) as the main product (first elution)) Bicyclobut[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester and methyl group as a secondary or by-product (second elution) (4-((3-methyl-2H-pyrazol[ 3,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester. Main product (methyl(4-(3-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid Third butyl ester):1 H NMR (400 MHz, methanol-d4) δ 8.99 (d, J = 1.1 Hz, 1H), 8.29 (d, J = 6.2 Hz, 1H), 7.52 (dd, J = 6.2, 1.2 Hz, 1H), 4.10 - 4.07 (m, 2H), 2.80 (s, 3H), 2.63 (s, 3H), 2.01 - 1.94 (m, 6H), 1.63 - 1.56 (m, 6H), 1.43 (s, 9H). MS (ES+): 385.2 (M+1)+. Minor or by-product (methyl(4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]oct-1-yl) ) butyl carbamic acid): 1H NMR (400 MHz, methanol-d4) δ 9.08 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 7.48 (dd, J = 6.3, 1.2 Hz, 1H), 4.19 (s, 2H), 2.81 (s, 3H), 2.77 (s, 3H), 2.07 - 1.97 (m, 6H), 1.70 - 1.62 (m, 6H), 1.43 (s , 9H). MS (ES+): 385.2 (M+1)+. Step 3: Use H-Cube: 100 ° C, 15 bar H2 , 10% Pd/C, 1 mL/min flow rate, methyl (4-((3-methyl-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[ 2.2.2] Octyl-1-octylamine carboxylic acid tert-butyl ester (233 mg, 0.606 mmol) was converted to the desired product, methyl (4-((3-methyl-4,5,6,7-tetra) Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG10). This product was used directly without purification. RT (Method 2): 1.7 minutes, MS (ES+): 389.3 (M+1)+.table 4 : extra tail base Head base The head group intermediates used to obtain the compounds of the present invention are shown in Table 5 and the synthesis thereof is shown below. The synthesis of certain reagents used to obtain such intermediates is also described below unless purchased.table 5 : head base Synthesis of 1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl trifluoromethanesulfonate (HG7)Step 1: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-5-amine and ethyl acetate in acetic acid was stirred at room temperature overnight. The reaction was concentrated in vacuo and then dissolved in DOWTH MeOH and heated to 230 ° C in a sealed vessel. The reaction was maintained at this temperature for 40 minutes and then cooled to room temperature. This reaction is performed by column chromatography (SiO2 , ISCO, 0-15% MeOH in dichloromethane) was purified to afford the desired phenol used directly in the next step. Step 2: To a solution of 1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1.895 g, 7.04 mmol) at 0 °C A solution of DCM (100 mL, 3.33 parts) and THF (30 mL, 1 part) was added triethylamine (7.36 mL, 52.8 mmol), followed by trifluoromethanesulfonic anhydride (2.97 mL, 17.59 mmol). The reaction was gradually warmed to room temperature over 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The organic phase was washed with brine and dried. The crude product was purified by silica gel chromatography eluting with 0% to 50% ethyl acetate in hexane to give 1-(4-methoxybenzyl)-6-methyl-1H trifluoromethanesulfonate. Pyrazolo[3,4-b]pyridin-4-yl ester (HG7). RT (LC/MS Method 2): 2.79 minutes. For C16 H14 F3 N3 O4 (M+H+), ESIMS calc. Synthesis of 4-chloro-2,8-dimethyl-1,7-naphthyridine (HG10)Intermittently adding methylmagnesium bromide (4.53 mL) to a solution of 4-chloro-2-methyl-1,7-naphthyridine (405 mg, 2.267 mmol) in THF (10 mL) over 30 min. , 13.60 mmol, 3 M in diethyl ether). The reaction changed from light brown to a dark green suspension. After stirring overnight, the reaction was stopped and then by adding saturated NH4 Cl (10 mL) was quenched andEtOAcEtOAcEtOAc EtOAc was washed with brine (5 mL) over Na2 SO4 It was dried and evaporated to give the desired crude product 4-chloro-2,8-dimethyl-7,8-dihydro-1,7-naphthyridine. MS 195.1 (M+1), RT (LC/MS Method 1) 0.94 min. Contains by-product MS 193.1 (M+1), RT (LC/MS Method 1) 0.85 min. This crude product was used in the next step without purification. The crude 4-chloro-2,8-dimethyl-7,8-dihydro-1,7-naphthyridine (440 mg, 2.260 mmol) from above was dissolved in DCM (20 mL). Add DDQ (513 mg, 2.260 mmol). The mixture was sonicated for 2 minutes. LCMS showed the reaction was completed. The mixture was diluted with EtOAc (50 mL) and filtered over EtOAc. The filter cake was washed with EtOAc (50 mL). The organics were evaporated to give a black residue. Purification of the crude product by flash chromatography (EtOAc: EtOAc / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc 0.82 minutes. (method 1). Synthesis of 4-chloro-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine (HG13)Step 1: A mixture of 2.5 g of 1-ethyl-1H-pyrazole-5-amine (22.5 mmol), 23.4 g (180 mmol) of 3-oxooxybutyrate and 1.35 g (22.5 mmol) of AcOH Vapourtec R2C+/R4 (dissociation pressure set to 40 bar; SS tube reactor; solution pressure set to 250 psi BPR) was used in the flow at 250 ° C at a flow rate of 0.2 mL/min in dioxane. The reaction was quenched with MeOH (flow rate 0.25 mL/min). The resulting solution was concentrated and triturated in EtOAc to afford 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol. RT 0.95 minutes (method 2). MS (M+1): 178.2. Step 2: 1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (1 g, in anisole (8 mL) at 130 °C 5.64 mmol) and POCl3 The sealed container (0.631 mL, 6.77 mmol) was heated for 2 hours. The reaction was allowed to cool and the solvent was removed in vacuo and dried to afford 4-chloro-l-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine (HG13). RT 0.52 min (LC/MS Method 2). MS (M+1): 196.6.Synthesis of exemplary compounds Example 1 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra Synthesis of Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1) step 1 : To (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] Addition of 4-bromo-1,6-dimethyl-1H-pyrazolo[3,4-b] to a pressure flask of oct-1-ylamine carboxylic acid tert-butyl ester (TG3) (0.565 g, 42.5 mmol) Pyridine (HG1) (0.94 g, 2.5 mmol), cesium carbonate (1.63 g, 5.0 mmol), Pd2 (dba)3 (0.057 g, 0.062 mmol), RuPhos (0.14 g, 0.3 mmol) and THF (25 mL). The mixture was heated at 80 ° C for 18 hours to completion and then cooled to room temperature. The mixture was diluted in ethyl acetate and water. After stratification, the aqueous layer was extracted once more with ethyl acetate. Combine two organic layers in MgSO4 Dry over, filter and concentrate in vacuo. The residue was subjected to flash chromatography using 0 to 100% B/A (A = heptane; B = 25% ethanol in ethyl acetate) to dissolve (4-((5-(1,6-dimethyl) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine Purification of -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester:1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 6.27 (s, 1H), 4.49 (s, 2H), 4.38 - 4.25 (m, 1H), 4.11 (s, 3H), 3.94 (t, J = 5.5 Hz, 2H), 3.70 (s, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.62 (s, 3H), 2.25 (s, 3H), 1.89 - 1.75 (m, 6H), 1.58 (m, 6H), 1.42 (s, 9H); for C29 H72 N7 O2 (M+H+ ), MS calculated value 520.34, measured value 520.4.step 2 : To (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-) Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (1.5 g, 1.45 mmol) A 500 mL round bottom flask was charged with methanol (6 mL) then 4N HCl (7.2 mL, 28.9 mmol) in dioxane. The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was batch treated with isopropanol at 70 ° C to dissolve all solids. The solution was allowed to naturally cool to room temperature and aged for 18 hours. The solid was then filtered and the filtrate was concentrated and the crystallization process was repeated. The two batches were combined and dried under vacuum at 40 °C for 18 hours to provide 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine) as the HCl salt. 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] octyl 1-amine (Compound No. 1 - HCl):1 H NMR (400 MHz, CD3 OD) δ 8.51 (s, 1H), 6.88 (s, 1H), 5.06 - 4.92 (m, 2H), 4.24 (s, 2H), 4.11 (s, 3H), 3.97 (s, 2H), 3.10 (t , J = 5.6 Hz, 2H), 2.69 (s, 3H), 2.38 (s, 3H), 1.88 - 1.59 (m, 12H); MS (M+H+ ), measured value 420.3.step 3 : Add Ambersep 900OH (17 ml, 0.8 meq/mL, pre-washed with 60 mL MeOH) to 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4) -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2 .2] A solution of oct-1-amine (Compound No. 1 - HCl) (1.53 g, 2.7 mmol) in MeOH (100 mL). The mixture was stirred at room temperature for 1 hour then filtered, washed with 50 mL MeOH and concentrated. The crude product was added (by solid loading) to a 12 g silica gel column and used to dissolve in 2 to 9% MeOH (containing a small amount of ammonia) in DCM. The fractions were collected and concentrated to give the product as a free base 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1):1 H NMR (400 MHz, CD3 OD) δ 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J = 5.6 Hz, 2H), 3.73 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.55 (s, 12H); MS (M+H+ ) 420.3. Example 2 4-((3-Methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound 2) and 4-((5-(1-(4-)) Oxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole Synthesis of [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound 53) Step 1: (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] Octyl-1-yl)carbamic acid tert-butyl ester (TG3) (110 mg, 0.294 mmol), trifluoromethanesulfonate 1-(4-methoxybenzyl)-6-methyl-1H-pyridyl Zyrazolo[3,4-b]pyridin-4-yl ester (HG7) (118 mg, 0.294 mmol), DIPEA (0.154 mL, 0.881 mmol) and BuOH (0.05 mL) were added to the reaction vial and then at 120 ° C Stir for 3 hours. The reaction mixture was purified by HPLC to give (4-((5-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl) --3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl a third butyl carbamate. RT (Method 2): 2.29 minutes, ESIMS m/z 626.4 (M+ + 1). Step 2: To (4-((5-(1-(4-methoxybenzyl))-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid Hydrochloric acid (0.879 mL, 5.27 mmol) was added to a solution of tributyl ester (110 mg, 0.176 mmol) in MeOH (1 mL). The reaction was stirred at 25 ° C for 16 hours and then dried to give 4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazole) as a HCl salt. ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo [2.2.2] Oct-1-amine (compound No. 53). RT (Method 1): 1.28 minutes, ESIMS m/z 526.3 (M+ + 1). Step 3: Add 4-((5-(1-(4-methoxybenzyl))-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl to a 20 mL pressure tube )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound 53) (80 mg, 0.152 mmol), cysteine (36.9 mg, 0.304 mmol) and TFA (2 mL). The mixture was heated at 75 °C for 2 hours and then cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to give 4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6, 7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 2). ESIMS m/z 406.2 (M+ + 1);1 H NMR (400 MHz, methanol-d4 ) δ 8.09 (s, 1H), 6.34 (s, 1H), 4.44 (s, 2H), 3.88 (t, J = 5.6 Hz, 2H), 3.63 (s, 2H), 3.56 (s, 4H), 2.80 (t, J = 5.6 Hz, 2H), 2.41 (s, 3H), 2.13 (s, 3H), 1.44 (s, 12H). Example 3 4-((3-Methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 3) and (4-((3-methyl-5-(2-methyl-1), 7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octyl- Synthesis of 1-Butylaminocarbamic acid tert-butyl ester (Compound No. 147) Step 1: Add (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo) to the reaction vial [2.2.2] Octyl-1-yl)carbamic acid tert-butyl ester (TG3) (105 mg, 0.280 mmol), 4-chloro-2-methyl-1,7-naphthyridine (HG9) (50 mg, 0.280 mmol), DIPEA (0.147 mL, 0.840 mmol) and BuOH (0.1 mL). The reaction was stirred at 120 °C for 3 h, diluted with MeOH and purified by HPLC. Pooling dissolving parts, using Na2 CO3 Neutralize and then extract with ethyl acetate to give (4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (Compound No. 147).1 H NMR (400 MHz, DMSO-d6 ) δ 9.53 (s, 1H), 8.73 (d, J = 5.9 Hz, 1H), 8.34 - 7.92 (m, 2H), 7.39 (s, 1H), 4.68 (s, 2H), 4.03 (t, J = 5.2 Hz, 2H), 3.72 (s, 2H), 3.08 (s, 2H), 2.78 (s, 3H), 2.51 (s, 9H), 2.12 (s, 3H), 1.80 - 1.45 (m, 12H). ESIMS m/z 518.0 (M+ + 1). Step 2: To (4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazole) a solution of [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (124 mg, 0.240 mmol) in MeOH (1 mL) Hydrochloric acid (1.200 mL, 7.20 mmol) was added. The reaction was stirred at 25 ° C for 16 hours. The reaction was dried to give 4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetrahydro-1H as a HCl salt. Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 3). ESIMS m/z 417.2 (M+ + 1);1 H NMR (400 MHz, DMSO-d6 ) δ 9.53 (s, 1H), 8.73 (d, J = 5.9 Hz, 1H), 8.16 - 8.05 (m, 4H), 7.39 (s, 1H), 4.70 (s, 2H), 4.03 (t, J = 5.6 Hz, 2H), 3.72 (s, 2H), 3.13 - 3.03 (m, 2H), 2.78 (s, 3H), 2.12 (s, 3H), 1.75 - 1.63 (m, 6H), 1.60 - 1.49 (m , 6H). Example 4 4-((3-Methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 4) and (4-((3-methyl-5-(2)) -methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl Synthesis of methyl)biscyclobut[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (compound No. 146)Step 1: Add (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo) to the reaction vial [2.2.2] Octyl-1-yl)carbamic acid tert-butyl ester (TG3) (67.0 mg, 0.179 mmol), 4-chloro-2-methyl-7H-pyrrolo[2,3-d]pyrimidine ( HG14) (30 mg, 0.179 mmol), DIPEA (0.094 mL, 0.537 mmol) and BuOH (0.1 mL). The reaction was stirred at 120 °C for 3 hours and then diluted with MeOH and purified by HPLC to give (4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d) Pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- Tertiary butyl carbamate (compound No. 146). RT (Method 2): 2.11 minutes. MS (ES+): 507.3 (M+1)+. Step 2: To (4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro) -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (35 mg, 0.075 mmol) in MeOH ( Hydrochloric acid (0.445 mL, 2.67 mmol) was added to the solution in 1 mL). The reaction was stirred at 25 ° C for 16 hours and then dried to give 4-((3-methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4) as HCl salt. -yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (No. 4 Compound). ESIMS m/z 406.2 (M+ + 1);1 H NMR (400 MHz, methanol-d4 ) δ 7.36 (d, J = 3.5 Hz, 1H), 7.08 (d, J = 3.6 Hz, 1H), 5.18 (s, 2H), 4.47 (t, J = 5.3 Hz, 2H), 4.17 (s, 2H) ), 3.16 (t, J = 5.3 Hz, 2H), 2.71 (s, 3H), 2.52 (s, 3H), 1.90 - 1.66 (m, 12H). Example 5 4-((5-(1,6-Dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro Synthesis of -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 5)Step 1: Add (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo) to the reaction vial [2.2.2] Octyl-1-yl)carbamic acid tert-butyl ester (TG3) (62.2 mg, 0.166 mmol), 4-chloro-1,6-dimethyl-1H-pyrrolo[2,3-b Pyridine (HG15) (30 mg, 0.166 mmol), RuPhos (9.30 mg, 0.020 mmol), ginseng (dibenzylideneacetone) dipalladium (0) (7.60 mg, 8.30 μmol), Cs2 CO3 (108 mg, 0.332 mmol) and THF (2 mL). The reaction was stirred at 75 ° C for 18 hours. The reaction is complete. The reaction was diluted with ethyl acetate and filtered through Celite to remove salt. The filtrate was dried and the crude product was used directly in the next step. Step 2: To (4-((5-(1,6-Dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methyl-4,5,6,7) - tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (30 mg, 0.046 mmol) Hydrochloric acid (0.231 mL, 1.388 mmol) was added to a solution in MeOH (1 mL). The reaction was stirred at 25 ° C for 16 hours, then dried and purified by HPLC to yield -((5-(1,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl) )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 5): ESIMS m/z 419.2 (M+ + 1);1 H NMR (400 MHz, methanol-d4 ) δ 7.14 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 6.66 (s, 1H), 4.67 (s, 2H), 4.03 (t, J = 5.6 Hz, 2H ), 3.79 (s, 3H), 3.69 (s, 2H), 2.86 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.13 (s, 3H), 1.66 (dd, J = 10.9, 4.6 Hz, 6H), 1.56 (dd, J = 10.8, 4.7 Hz, 6H). Example 6 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)oxetan-3-amine (No. 6 Synthesis of compounds)To 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 1 from Example 1, 1.68 g, 4.0 mmol) in DCE Acetate (0.229 mL, 1.0 eq.) and oxetane-3-one (2.94 g, 10 eq.) were added to a solution (40 mL). The mixture was stirred at room temperature for 30 minutes and then sodium triethoxysulfonate (2.62 g, 3.0 eq.) was added. The mixture was then stirred overnight at room temperature. Add more oxetane-3-one (1.47 g, 5 equivalents), sodium triethoxy borohydride (1.3 g, 1.5 eq.) and 20 mL DCE and stir the mixture at room temperature. It was then treated with 40 mL of 1 N NaOH for 5 hours. The layers were separated and the aqueous layer was extracted with DCM / MeOH (5:1 v/v, 100 mL x 3). Combined organic layer in Na2 SO4 It was dried, filtered and concentrated to give a crude material. The crude product was added to a 40 g gold ruthenium rubber column and used for 0 to 50% (for 25 minutes) IPA (containing 0.02 M ammonia) in DCM. The fractions were collected and concentrated to give N-(4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4) ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)oxetane-3 -amine (compound No. 6): 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.60 (t, J = 6.8 Hz, 2H), 4.43 (s, 2H) ), 4.34 (t, J = 6.6 Hz, 2H), 4.04 (p, J = 7.2 Hz, 1H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H) ), 2.79 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.12 (s, 3H), 1.47 - 1.33 (m, 12H). MS (ES+): 476.3 (M+1)+. Example 7 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(dimethylamino)acetamidine Synthesis of Amine (Compound No. 7)To 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 1 from Example 1, 2.52 g, 6.0 mmol) and 2 DIPEA (2.1 mL, 2.0 eq.) was added to a mixture of <RTI ID=0.0>>> The resulting mixture was stirred at room temperature for 1 hour and then washed with 30 mL of water. The aqueous layer was extracted with DCM (100 mL x 3) and combined organic layers in Na2 SO4 It was dried, filtered and concentrated to give a crude material. The crude product was added to an 80 g gold ruthenium rubber column and used to dissolve from 0 to 50% (over 30 minutes) IPA (containing 0.02 M ammonia) in DCM. The fractions were collected and concentrated to give N-(4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4) ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(dimethyl Amino) acetamidine (Compound No. 7): 1H NMR (600 MHz, methanol-d4) δ 8.17 (s, 1H), 6.47 (s, 1H), 4.56 (s, 2H), 4.02 (s, 3H) , 3.99 (dd, J = 6.1, 5.1 Hz, 2H), 3.74 (s, 2H), 2.94 - 2.91 (m, 2H), 2.90 (s, 2H), 2.56 (s, 3H), 2.36 (s, 1H ), 2.30 (s, 6H), 2.25 (s, 3H), 1.94 - 1.87 (m, 6H), 1.63 - 1.57 (m, 6H). MS (ES+): 505.4 (M+1)+. Example 8 (S)-N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide Synthesis of (No. 8 compound)To 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (from compound No. 1 of Example 1) (42 mg, 0.1 mmol), Add HATU (45.6 mg, a mixture of (S)-4-(t-butoxycarbonyl)morpholine-3-carboxylic acid (25.4 mg, 0.11 mmol) and DIPEA (0.035 mL, 0.2 mmol) in 1.0 mL DMF 0.12 mmol), then stirred at room temperature for 30 minutes. LC-MS confirmed the completion of the reaction. Intermediate by mass induced HPLC (10 to 90% ACN in H)2 In O, it took 3.5 minutes to purify. The collected fractions were concentrated and the residue was dissolved in MeOH / 1,4-diosane (l. 4 M HCl (1.0 mL) in 1,4-dioxane was added and the mixture was stirred at room temperature for 1 hour, then concentrated and lyophilized to give (S)-N-(4- ((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide (compound No. 8). 1H NMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 7.92 (s, 1H), 6.88 (s, 1H), 5.06 - 4.91 (m, 2H), 4.25 (s, 2H), 4.19 - 4.09 (m, 4H), 4.03 - 3.89 (m, 4H), 3.78 - 3.56 (m, 4H), 3.22 (ddd, J = 12.9, 11.2, 3.7 Hz, 1H), 3.17 - 3.05 (m, 2H), 2.70 (s, 3H), 2.41 (s, 3H), 1.93 (dd, J = 8.9, 5.0 Hz, 6H), 1.72 - 1.54 (m, 6H). MS (ES+): 533.3 (M+1)+. Example 9 (R)-N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide Synthesis of (No. 9 compound)To 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (from compound No. 1 of Example 1) (42 mg, 0.1 mmol), Add HATU (45.6 mg, a mixture of (R)-4-(t-butoxycarbonyl)morpholine-3-carboxylic acid (25.4 mg, 0.11 mmol) and DIPEA (0.035 mL, 0.2 mmol) in 1.0 mL DMF 0.12 mmol), then stirred at room temperature for 30 minutes. LC-MS confirmed the completion of the reaction. Intermediate by mass induced HPLC (10 to 90% ACN in H)2 In O, it took 3.5 minutes to purify. The collected fractions were concentrated and the residue was dissolved in MeOH / 1,4-diosane (l. 4 M HCl (1.0 mL) in 1,4-dioxane was added and the mixture was stirred at room temperature for 1 hour, then concentrated and lyophilized to give (R)-N-(4- ((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide (Compound No. 9). 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 7.92 (s, 1H), 6.88 (s, 1H), 5.03 - 4.92 (m, 1H), 4.32 - 4.18 (m, 2H), 4.20 - 4.09 (m, 4H), 4.03 - 3.89 (m, 4H), 3.78 - 3.54 (m, 4H), 3.22 (ddd, J = 13.0, 11.2, 3.8 Hz, 1H), 3.15 - 3.05 (m, 2H ), 2.69 (s, 3H), 2.39 (s, 3H), 1.98 - 1.85 (m, 6H), 1.62 (dd, J = 10.3, 5.9 Hz, 6H). MS (ES+): 533.3 (M+1)+. Example 10 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-oxa-6-aza Spiro[3.3]heptane (compound No. 10) and 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine-7-) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound 26) SynthesisStep 1: 7-Chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (HG4) (263 mg, 1.335 mmol), (4-((3-) 4-,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid A mixture of butyl ester (TG3) (500 mg, 1.335 mmol) and DIPEA (0.233 mL, 1.335 mmol) in 2-propanol (30 mL) was warmed to 100 ° C for 1 hour. After treatment and column chromatography (eluent: 2:1 EtOAc:hexane), 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazole) was obtained. [4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] Octan-1-yl) carbamic acid tert-butyl ester. LC-MS: MS (ESI+): 495. Step 2: (4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5, 3,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester was subjected to Example 4 The same conditions as described in Step 2 to give 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 26).1 H NMR (400 MHz, methanol-d4 ) δ 4.96 (s, 2H), 4.31 (t, J = 5.6 Hz, 2H), 4.24 (s, 3H), 3.77 (s, 2H), 3.04-2.98 (m, 2H), 2.71 (s, 3H) , 2.53 (s, 3H), 2.21 (s, 3H), 1.80-1.62 (m, 12H). MS (ES+): 435.4 (M+1)+. Step 3: (60 mg, 0.138 mmol) 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound 26) 101 mg (0.414 mmol) 1,1-bis(bromomethyl)cyclobutane and K2 CO3 A mixture of (95 mg, 0.690 mmol) in 2-propanol (10 mL) was warmed to 120 <0>C for 72 hours. After cooling to room temperature, 2-propanol was evaporated, water was added and the mixture was extracted with EtOAc. Combine organic layers, dry (Na2 SO3 ) and concentrated. The residue was purified by preparative LC-MS to give 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine) -7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl) 2-oxa-6-azaspiro[3.3]heptane (compound No. 10).1 H NMR (400 MHz, methanol-d4 ) δ 4.70 (s, 4H), 4.52 (s, 2H), 4.11 (s, 3H), 3.86 (t, J=5.7 Hz, 2H), 3.71 (s, 2H), 3.39 (s, 4H), 2.99 (t, J = 5.5 Hz, 2H), 2.59 (s, 3H), 2.50 (s, 3H), 2.18 (s, 3H), 1.58-1.40 (m, 12H). MS (ES+): 517.3 (M+1)+. Example 11 4-((5-(6-(4-Fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4, Synthesis of 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 83)Step 1: 4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (HG16) (40 mg, 0.197 mmol), (4-((3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG3) (70 mg, 0.187 mmol), Pd2dba3 (10 mg, 10.92 μmol), RuPhos (10 mg, 0.021 mmol) and Cs2 CO3 (65 mg, 0.199 mmol) was mixed in dioxane (5 mL) and stirred at 120 ° C for 6 h. After treatment and preparative LC-MS, (4-((5-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)carbamic acid tert-butyl ester. Step 2: 4-((5-(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6 , 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (20 mg, 0.037 Ment), (4-fluorophenyl)boronic acid (10 mg, 0.071 mmol), PdCl2 (dppf).CH2 Cl2 Adduct (6 mg, 7.35 μmol) and K2 CO3 (20 mg, 0.145 mmol) was mixed in dioxane (3 mL) and stirred at 110 ° C for 6 h. After treatment and preparative LC-MS, (4-((5-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) --3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl a third butyl carbamate. Step 3: 4-((5-(6-(4-Fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)carbamic acid tert-butyl The ester (10 mg, 0.017 mmol) and 4 N HCl (0.152 mL, 4.99 mmol) were taken in MeOH (1 mL) and stirred at 50 ° C for 5 hr. After treatment and preparative LC-MS, 4-((5-(4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl) was obtained. 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine ( Compound No. 83).1 H NMR (400 MHz, methanol-d4 ) δ 8.55 (dd, J=8.7, 5.7 Hz, 2H), 8.27 (s, 1H), 7.21 (t, J=8.8 Hz, 2H), 4.97 (s, 2H), 4.38 (brs, 2H), 4.06 (s, 3H), 3.80 (s, 2H), 2.92 (t, J = 5.4 Hz, 2H), 2.29 (s, 3H), 1.80-1.60 (m, 12H). MS (ES+): 501.3 (M+1)+. Example 12 4-(4-(1-(4-Aminobicyclo[2.2.2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-1H-pyrazolo[ Synthesis of 4,3-c]pyridine-5(4H)-yl)pyridin-2-yl)benzonitrile (Compound No. 84)Step 1: 2-Chloro-4-fluoropyridine (130 mg, 0.988 mmol), (4-((3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (TG3) (370 mg, 0.988 mmol) and DIPEA (130 mg, 1.006 mmol) It was stirred in DMA (5 mL) at 150 ° C for 4 hours. After treatment and column chromatography (2:1 EtOAc:hexane), 4-((5-(2-chloropyridin-4-yl)-3-methyl-4,5,6,7- Tert-butyl-1H-hydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylate. Step 2: (4-((5-(2-Chloropyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] Pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester (25 mg, 0.051 mmol), (4-cyanophenyl)boronic acid (15 mg, 0.102 mmol) ), PdCl2 (dppf).CH2 Cl2 Adduct (5 mg, 6.12 μmol) and K2 CO3 (25 mg, 0.181 mmol) was mixed in dioxane (3 mL) and stirred at 120 ° C for 17 h. After treatment and preparative LC-MS, (4-((5-(2-(4-cyanophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro) -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester. Step 3: (4-((5-(2-(4-Cyanophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole) [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)carbamic acid tert-butyl ester (20 mg, 0.036 mmol) and 4 N HCl (0.220 mL, 7.24 Methyl acetate was mixed in MeOH (1 mL) and stirred at 50 ° C for 3 h. After treatment and preparative LC-MS, 4-(4-(1-aminobicyclo[2.2.2]oct-1-yl)methyl)-3-methyl-6,7-di Hydrogen-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)pyridin-2-yl)benzonitrile (compound No. 84). 1H NMR (400 MHz, methanol-d4) δ 8.25 (d, J = 7.4 Hz, 1H), 8.08-7.97 (m, 4H), 7.56 (brs, 1H), 7.36 (m, 1H), 4.71 (s, 2H), 4.09 (brs, 2H), 3.79 (s, 2H), 2.93 (t, J=5.4 Hz, 2H), 2.25 (s, 3H), 1.82-1.60 (m, 12H). MS (ES+): 453.3 (M+1)+. Example 13 5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidin-1-yl) Synthesis of Bicyclo[2.2.2]oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Compound No. 58)4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1 from Example 1) (23 mg, 0.055 mmol) with carbonic acid Potassium (22.73 mg, 0.164 mmol), 1,4-dibromobutane (59.2 mg, 0.274 mmol) and ethanol (548 μL). The mixture was heated to 120 ° C by microwave irradiation for 30 minutes. The mixture was diluted with ethyl acetate and 1 N NaOH. After extraction, the aqueous layer was back extracted twice with ethyl acetate. Combine organic layers with MgSO4 Dry and concentrate in vacuo. The residue was loaded onto a 4 g cartridge column using 0 to 50% IPA/DCM with 3% ammonia as the modifier to obtain 5-(1,6-dimethyl-1H-pyrazole[3,4- b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,5,6, 7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine (Compound 58). 1H NMR (400 MHz, methanol-d4) δ 8.06 (s, 1H), 6.36 (s, 1H), 4.45 (s, 2H), 3.99 (s, 3H), 3.89 (m, 2H), 3.64 (s, 2H), 2.81 (m, 2H), 2.64 (s, 4H), 2.45 (s, 3H), 2.13 (s, 3H), 1.68 (s, 4H), 1.63 - 1.35 (m, 12H). ESIMS (M+H+) 475.2. Example 14 4-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, Synthesis of 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine (Compound No. 59)4-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine was obtained using the method described in Example 13, except 1-Bromo-2-(2-bromoethoxy)ethane (63.6 mg, 0.274 mmol) was substituted for 1,4-dibromobutane. 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 3.99 (d, J = 9.5 Hz, 5H), 3.73 (s, 2H) , 3.68 - 3.51 (m, 4H), 2.91 (t, J = 5.4 Hz, 2H), 2.23 (s, 3H), 1.57 (m, 12H). ESIMS (M+H+) 491.0. Example 15 1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H-pyrazolo[ Synthesis of 3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Compound No. 119)4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (from compound No. 1 of Example 1) (55 mg, 0.131 mmol) Add 1 drop of phosphorous acid (pH: ~1) to water (807 μL). Paraformaldehyde (4.72 mg, 0.157 mmol) and glyoxal (18.04 μL, 0.157 mmol) 40% were added to water and the resulting mixture was heated to 80 °C. A solution of ammonium chloride (8.41 mg, 0.157 mmol) dissolved in water (202 μL) was added dropwise over 10 minutes and the resulting mixture was heated to 110 ° C for 18 hours, LC-MS showed still ~50% unconverted Starting material. Additional 47 mg paraformaldehyde, glyoxal (18 mL) and NH4 Cl (84 mg) was added to the mixture (let it complete). The mixture was heated at 110 ° C for 18 hours. Use Na2 CO3 The reaction mixture was adjusted to pH 8 to 9 and extracted twice with DCM. Concentrate the organic layer and load it onto a 4 g tantalum tube column for 0 to 50% IPA in DCM at 3% NH3 As a modifier to provide 1-((4-(1H-imidazol-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H- Pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (Compound 119) . 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.55 (s, 2H), 4.01 (s, 3H), 3.91 (m, 2H), 3.73 (s, 2H), 3.68 - 3.51 (m, 4H), 2.91 (m, 2H), 2.55 (m, 4H), 2.52 (s, 3H), 2.23 (s, 3H), 1.57 (m, 12H). ESIMS (M+H+) found 471.6. Example 16 4-((3-Methyl-5-(6-methyl-1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5 Synthesis of 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 140)In a 20 mL round bottom flask containing 3 mL of DMF at 0 ° C (4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridine-) 4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amine Tert-butyl formate and K2 CO3 Mixture of CD3I (27.7 μL CD)3 I 0.1 mL solution in 1 mL DMF). The resulting mixture was slowly warmed to room temperature and stirred overnight. The mixture was then concentrated and purified by ISCO (4 g EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c Pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester. RT = 1.13 minutes (method 1), MS (ES+): 524.3 (M+1)+. To 11.5 mg (0.022 mmol) (4-((3-methyl-5-(6-methyl-1-(methyl-d3)-1H-pyrazolo[3,4-b]pyridine-4- -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid To a solution of tributyl ester in 1 mL of dioxane and 0.1 mL of MeOH was added 1 mL of 4 M HCl in dioxane. The resulting mixture was stirred at room temperature for 1 hour, then concentrated and lyophilized to give the desired product (comp. 140) as HCl salt. 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 6.88 (s, 1H), 5.04 - 4.94 (m, 2H), 4.25 (s, 2H), 3.98 (s, 2H), 3.78 - 3.56 (m, 2H), 3.11 (d, J = 5.1 Hz, 2H), 2.70 (s, 3H), 2.39 (s, 3H), 1.85 - 1.66 (m, 12H). MS (ES+): 423.3 (M+1)+. Example 17 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra Synthesis of hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2]oct-1-amine (compound No. 43)To 4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 in a 100 mL round bottom flask 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (from compound No. 1 of Example 1) DIPEA (0.13 mL, 97 mg, 0.75 mmol) was added in THF / MeOH (5 mL / 1.5 mL). The mixture was stirred at room temperature for 10 minutes and then formaldehyde (0.037 mL, 37% by weight in water) was added. The resulting mixture was stirred at room temperature for 30 minutes and then NaBH was added.3 CN (157 mg, 2.5 mmol). The mixture was then stirred at room temperature overnight, quenched by the addition of 2.0 mL water and then extracted with DCM. Combined organic layer and then Na2 SO4 Dry on top and then concentrate. The crude product was added to a 4 g silica gel column and used to dissolve in 0 to 8% MeOH (containing a very small amount of ammonia) in DCM. The fractions were collected and concentrated, then lyophilized to give the desired product 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2.2] octyl -1-amine. 1H NMR (600 MHz, methanol-d4) δ 8.07 (s, 1H), 6.39 (s, 1H), 4.47 (s, 3H), 3.86 (s, 5H), 3.63 (d, J = 2.5 Hz, 2H) , 2.78 (t, J = 5.6 Hz, 2H), 2.58 (s, 6H), 2.41 (s, 3H), 2.07 (s, 3H), 1.71 - 1.65 (m, 6H), 1.55 - 1.49 (m, 6H) ). MS (ES+): 448.4 (M+1)+. Example 18 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, Synthesis of 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)methanesulfonamide (Compound No. 48)57 mg (0.1 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) at 0 °C 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 1) and 39 Mg (0.052 mL, 0.3 mmol) 14.9 mg (10.1 μL, 0.13 mmol) of methanesulfonyl chloride was added to a mixture of DIPEA in 2 mL DCM. The resulting mixture was slowly warmed to room temperature and stirred for 2 hours. The crude product was added (by solid loading) to a 4 g silica gel column and used to dissolve from 0 to 7% MeOH in MeOH (containing a very small amount of ammonia) and further purified by mass-induced HPLC. The fractions were collected, 1.0 mL of 1 N aqueous HCl solution was added, then concentrated and lyophilized to give N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4 -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2 .2] Oct-1-yl) Mesylate (Compound No. 48). 1H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 6.89 (s, 1H), 5.06 - 4.94 (m, 2H), 4.25 (s, 2H), 4.12 (s, 3H), 3.98 ( s, 2H), 3.18 - 3.06 (m, 2H), 2.94 (s, 3H), 2.70 (s, 3H), 2.43 (s, 3H), 1.96 - 1.85 (m, 6H), 1.67 - 1.57 (m, 6H). MS (ES+): 498.2 (M+1)+. Example 19 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]oct-1-amine (compound No. 50) and (4-(( 5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole Synthesis of [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)(methyl)aminecarboxylic acid tert-butyl ester (compound No.49)Step 1: 4-Bromo-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine (HG1) (67 mg, 0.295 mmol), (4-((3-methyl-4) ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butylmethyl ester ( TG10) (115 mg, 0.295 mmol), Pd2 Dba3 (6.8 mg, 0.074 mmol), RuPhos (17 mg, 0.035 mmol) and Cs2 CO3 The mixture (192 mg, 0.590 mmol) in THF was washed with argon and then heated to 75 ° C for 15 hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate and water. The layers were separated and the aqueous extracted with EtOAc. Combined organic layer in Na2 SO4 Dry over, filter in vacuo and concentrate. The crude product was added to a 12 g silica gel column and used to dissolve from 0 to 5% methanol in DCM. The fractions were collected and concentrated to give (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)(methyl)aminecarboxylic acid tert-butyl Ester (compound No. 49). 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 5H), 3.72 (s, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.80 (s, 3H), 2.55 (s, 3H), 2.23 (s, 3H), 2.04 - 1.91 (m, 6H), 1.60 - 1.52 (m, 6H), 1.43 (s , 9H). MS (ES+): 534.4 (M+1)+. Step 2: To 90 mg (0.169 mmol) (4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)(methyl)aminecarboxylic acid To a solution of the third butyl ester (Compound No. 49) in dioxane / MeOH (1 mL / 1 mL) was added HCl (2 mL of 4 M solution in dioxane). The resulting mixture was stirred at room temperature for 2 hours. LC-MS showed the reaction was completed. The reaction mixture was concentrated and the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Filter and wash with 10 mL MeOH then concentrate. The crude product was added to a 4 g silica gel column and used for 2 to 9% MeOH (with a small amount of ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to give 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]oct-1-amine (No. 50 Compound). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.36 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.88 (t, J = 5.8 Hz, 2H) , 3.64 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H). MS (ES+): 434.3 (M+1)+. Example 20 (4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid 1-methylcyclopropyl ester (Compound No. 51) SynthesisTo 57 mg (0.1 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1) in 1 mL DMA DIPEA (52 mg, 0.4 mmol) was added to the suspension followed by 1-methylcyclopropyl (4-nitrophenyl)carbonate (24 mg, 0.1 mmol). The resulting mixture was heated at 150 ° C for 2 hours under microwave irradiation. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer is washed with brine and applied to Na2 SO4 Dry and concentrate. The crude product was added to a 4 g silica gel column and used to dissolve from 0 to 8% MeOH in DCM. The fractions are collected and concentrated and then lyophilized to give (4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)carbamic acid 1-methyl Cyclopropyl ester (compound No. 51). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.6 Hz, 2H) , 3.61 (s, 2H), 2.80 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.74 - 1.63 (m, 6H), 1.50 - 1.40 (m, 6H) ), 1.35 (s, 3H), 0.71 - 0.61 (m, 2H), 0.48 - 0.41 (m, 2H). MS (ES+): 518.3 (M+1)+. Example 21 N-(2,2-Difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3 -methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (61) Synthesis of compounds)To 29.4 mg (0.07 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1) and 18.1 mg (0.024 mL) , 0.14 mmol) 2,2-difluoroethyl trifluoromethanesulfonate (16.5 mg (10.3 μL, 0.077 mmol) was added to a mixture of DIPEA in 1 mL THF. The mixture was stirred at 85 ° C for 2 hours. MS showed the desired product and the reaction was completed. The crude product was directly added to a 4 g silica gel column and used to dissolve in 2 to 9% MeOH (containing a small amount of ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to yield N -(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 61). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.36 (s, 1H), 5.79 (tt, J = 55.9, 4.1 Hz, 1H), 4.44 (s, 2H), 3.89 (m, 5H), 3.64 (s, 2H), 2.94 - 2.75 (m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 1.49 (s, 12H). MS (ES+): 484.2 (M+1) ) +. Example 22 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2- Methoxyethyl)bicyclo[2.2.2]oct-1-amine (compound No. 69) and 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-double Synthesis of (2-methoxyethyl)bicyclo[2.2.2]oct-1-amine (Compound No. 70)21 mg (0.05 mmol) of 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) at 120 ° C under microwave irradiation -methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (No. 1 A mixture of 43 mg (0.031 mL, 0.250 mmol) of 1-bromo-2-ethoxyethane and 21 mg (0.150 mmol) of potassium carbonate in EtOH (1 mL). LC-MS showed the desired product 1 but the reaction was not completed. The solvent was changed to IPA and heated at 110 ° C overnight in an oil bath. LC-MS showed two products. The crude product was added to a 12 g silica gel column and used to dissolve from 0 to 30% IPA (containing 1% ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to give 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-ethoxyethyl)bicyclo[2.2.2] octane 1-amine (compound No. 69) and 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-ethoxyethyl)bicyclo[2.2. 2] Oct-1-amine (compound No. 70). Compound No. 69: 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 8.05 (d, J = 8.2 Hz, 0H), 8.04 (s, 0H), 7.54 (d, J = 8.1 Hz, 0H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H), 3.73 (s, 2H), 3.35 (s, 2H), 2.98 (s, 3H), 2.94 (s, 3H), 2.90 (t, J = 5.6 Hz, 2H), 2.55 (s, 3H), 2.23 (s, 3H), 1.56 (s, 12H). MS (ES+): 505.4 (M+1)+. Compound No. 70: 1H NMR (400 MHz, methanol-d4) δ 8.15 (s, 1H), 6.45 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.97 (t, J = 5.5 Hz, 2H), 3.69 (s, 2H), 3.31 (d, J = 1.1 Hz, 6H), 2.90 (t, J = 5.6 Hz, 2H), 2.75 - 2.65 (m, 4H), 2.55 (s, 3H) ), 2.23 (s, 3H), 1.64 - 1.47 (m, 12H). MS (ES+): 536.4 (M+1)+. Example 23 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylbicyclo[2.2.2]oct-1- Synthesis of Amine (Compound No. 73)12 mg (0.028 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) at 150 ° C under microwave irradiation -methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]oct-1 -Amine (Compound No. 50), 19 mg (0.013 mL, 0.138 mmol) 1-bromo-2-methoxyethane and 11.5 mg (0.083 mmol) K2 CO3 The mixture in IPA was heated for 1 hour. The crude product was added directly to a 4 g silica gel column and used to dissolve from 0 to 30% IPA (containing 1% ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to give 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)-N-methylbicyclo[ 2.2.2] Oct-1-amine (compound No. 73). 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 6.46 (s, 1H), 4.54 (s, 2H), 4.00 (s, 3H), 3.98 (t, J = 5.7 Hz, 2H) , 3.72 (s, 2H), 3.43 (t, J = 5.8 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 2.63 (s, 2H), 2.55 (s, 3H), 2.23 (s, 6H), 1.67 - 1.49 (m, 12H). MS (ES+): 492.4 (M+1)+. Example 24 2-((4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)-N,N-dimethyl Synthesis of acetamide (compound No. 76).42.0 mg (0.1 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) at room temperature 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (compound No. 1), 18.3 A mixture of mg (0.11 mmol) of 2-bromo-N,N-dimethylacetamide and 65.2 mg (0.2 mmol) of cesium carbonate in 1 mL of DMF was stirred overnight. The crude product was added to a 4 g silica gel column and used to dissolve from 0 to 30% IPA (containing 1% ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to afford 2-((4-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino) -N,N-dimethylacetamide (compound No. 76). 1H NMR (400 MHz, methanol-d4) δ 8.17 (d, J = 1.8 Hz, 1H), 6.47 (s, 1H), 4.56 (s, 2H), 4.02 (s, 3H), 4.00 (t, J = 5.7 Hz, 2H), 3.76 (m, 2H), 3.56 (m, 2H), 3.03 - 2.95 (m, 6H), 2.92 (t, J = 5.6 Hz, 2H), 2.56 (s, 3H), 2.25 ( s, 3H), 1.73 - 1.56 (m, 12H). MS (ES+): 505.4 (M+1)+. Example 25 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-N-methyloxetane-3 Synthesis of Amine (Compound No. 77)To 2.1 mg (4.4 μmol N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)oxetane-3- Acetate (1.33 mL (1.26 μL, 0.022 mmol) and 10.9 mg (0.134 mmol) of formaldehyde was added to a solution of the amine (Compound No. 6) in THF (1 mL). The mixture was stirred at room temperature for 1 hour and then cyanide was added. Sodium borohydride. The resulting mixture was then stirred overnight at room temperature. The reaction was quenched by addition of 0.1 mL water and then concentrated. The crude product was then applied to a 4 g cartridge and used in 0 to 50% IPA in DCM. (containing 1% ammonia) was dissolved. The fractions were collected and concentrated and then lyophilized to provide N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine) 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] octyl -1-yl)-N-methyloxetan-3-amine (Compound No. 77). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.58 (t, J = 6.9 Hz, 2H), 4.47 (t, J = 7.0 Hz, 2H), 4.44 (s, 2H), 4.25 (q, J = 7.3 Hz, 1H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H), 3.61 (s, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.44 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H), 1.45 (s, 12H). MS (ES+) : 490.4 (M+1)+. Example 26 4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-methylpropyl)bicyclo [2.2.2] Synthesis of oct-1-amine (compound No. 101)Step 1: To a solution of 14.2 mg (0.12 mmol) of 2-methoxy-2-methylpropanoic acid in DMF (2 mL) was added HATU (45.6 mg, 0.12 mmol) and DIPEA (0.035 mL, 25.8 mg, 0.2 Mm). The mixture was stirred at room temperature for 5 minutes and then 42.0 mg (0.1 mmol) of 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-) was added. 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- Amine (compound No. 1). The resulting mixture was then stirred at room temperature for 1 hour. LC-MS showed the reaction was completed. The mixture was partitioned between EtOAc and water. The layers were separated and the aqueous extracted with EtOAc. Combined organic layer in Na2 SO4 Dry on top and then concentrate. The crude product was added to a 4 g silica gel column and used to dissolve from 0 to 50% IPA (containing 1% ammonia) in DCM. The fractions were collected and concentrated and then lyophilized to provide N-(4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) 4-,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-methyl Oxy-2-methylpropanamide. 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 6.77 (s, 1H), 6.51 (s, 1H), 4.58 (s, 2H), 3.96 (t, J = 5.4 Hz, 2H) , 3.94 (s, 3H), 3.64 (s, 2H), 3.12 (s, 3H), 2.84 (t, J = 5.6 Hz, 2H), 2.49 (s, 3H), 2.14 (s, 3H), 1.83 - 1.73 (m, 6H), 1.53 - 1.43 (m, 6H), 1.17 (s, 6H). MS (ES+): 520.3 (M+1)+. Step 2: 17 mg (0.033 mmol) N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) at 0 °C 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl) 6.5 mg (0.164 mmol) of LiAlH was added to the stirred solution of 2-methoxy-2-methylpropionamide in THF (1 mL)4 . The resulting mixture was then slowly warmed to room temperature and stirred overnight. After cooling at 0 ° C, the reaction was quenched with IPA then water and concentrated. The crude product was added (by solid loading) to a 4 g cartridge column and used to dissolve from 0 to 30% IPA (containing 1% ammonia) in DCM. The fractions were collected and concentrated and then further purified by mass-induced HPLC to afford 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy-2-methyl Propyl)bicyclo[2.2.2]oct-1-amine (compound No. 101) which was neutralized using Ambersep 900 OH (strongly basic anion exchanger). 1H NMR (600 MHz, methanol-d4) δ 8.05 (d, J = 1.1 Hz, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.90 - 3.85 (m, 2H), 3.64 (d, J = 6.3 Hz, 2H), 3.07 (s, 2H), 2.83 - 2.77 (m, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.57 - 1.46 (m , 12H), 1.07 (s, 6H). MS (ES+): 506.4 (M+1)+. Example 27 4-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-1-methylpiperazin-2-one ( Synthesis of Compound No. 104)Step 1: To 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7 -tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine (Compound No. 1) (121 mg, 0.246 mmol) in CPME The solution in (12.3 mL) was added methyl (2-triethoxyethyl)aminecarboxylic acid tert-butyl ester (63.8 mg, 0.369 mmol). The mixture was stirred at 25 ° C for 30 minutes and then sodium triethoxysulfonate (156 mg, 0.737 mmol) was added. The mixture was then stirred at 25 ° C for 3 hours. Concentrate the mixture and use 0 to 40% IPA in DCM at 2% NH3 It was purified as a modifier on a 4 g tantalum column to dissolve 88.6 mg (0.154 mmol) (2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4 -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2 .2] Octyl-1-amino)amino)ethyl)(methyl)aminecarboxylic acid tert-butyl ester. RT (Method 1): 1.26 minutes, MS (ES+): 577.4 (M+1)+. Step 2: 40 mg (0.069 mmol) of 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]]) at 150 ° C under microwave irradiation Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] Octyl-1-amino)ethyl)ethyl)(methyl)aminecarboxylic acid tert-butyl ester, 35.5 mg (0.024 mL, 0.208 mmol) of ethyl 2-bromoacetate and 10.5 mg (0.076 mmol) of potassium carbonate in EtOH ( The mixture in 1 mL) was heated for 1 hour. LC-MS showed the reaction was completed. The reaction was allowed to cool to room temperature, 1N aqueous NaOH solution was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was then diluted with 2 mL of water and the organic solvent was removed on a rotary evaporator using Et.2 O (3 mL) wash. The aqueous layer was then carefully acidified to ~pH 3 with 1N aqueous HCl. It was extracted with EtOAc and then extracted with DCM / MeOH, but most of the product remained in the aqueous phase based on LC-MS. Both the aqueous phase and the organic phase are concentrated and then purified by mass induced HPLC to provide 2-((2-((t-butoxycarbonyl))(methyl)amino)ethyl)(4-((5) -(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)acetic acid. RT (Method 2): 1.72 minutes, MS (ES+): 634.8 (M+1)+. Step 3: To 27.0 mg (0.043 mmol) 2-((2-((t-butoxycarbonyl))(methyl)amino)ethyl)(4-((5-(1,6-dimethyl) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- To a mixture of 1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)acetic acid in 1 mL of 1,4-dioxane, 0.3 mL of MeOH was added to obtain a clear solution. 4 M HCl in dioxane was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was completed. The mixture was concentrated and the residue was dissolved in EtOAc EtOAc EtOAc (EtOAc) The resulting mixture was stirred at 0 ° C for 30 minutes. LC-MS showed the reaction was completed. Crude product by mass induced HPLC (10 to 20% ACN in H2 Purification in O, 3.5 minutes) followed by neutralization with a basic resin to provide 4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4) -yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1 -yl)-1-methylpiperazin-2-one (compound No. 104). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H) , 3.62 (s, 2H), 3.17 (dd, J = 6.3, 4.5 Hz, 2H), 3.08 (s, 2H), 2.80 (m, 5H), 2.66 (dd, J = 6.3, 4.5 Hz, 2H), 2.44 (s, 3H), 2.13 (s, 3H), 1.48 (tq, J = 9.4, 6.4, 4.7 Hz, 12H). MS (ES+): 517.3 (M+1)+. Example 28 1-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-4-methylpiperazin-2-one ( Synthesis of Compound No. 108)Step 1: 80 mg (0.139 mmol) at 0 ° C (2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4-) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- a solution of tert-butyl)amino)ethyl)(methyl)aminecarboxylate (Example 27, Step 1) and 36 mg (0.048 μL, 0.277 mmol) of DIPEA in 1.0 mL of DCM. Bromine (0.062 mL, 0.694 mmol) in DCM (1.0 mL). The resulting mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction was then quenched by the addition of 0.1 mL water and concentrated. The crude product was added to a 4 g silica gel column and used to elute from 0 to 30% IPA (containing 0.02 M ammonia) in DCM. The fractions were collected and concentrated to provide (2-(2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) --3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl Ethylamino)ethyl)(methyl)aminecarboxylic acid tert-butyl ester. RT (Method 1): 1.45 minutes. MS (ES+): 701.2, 700.3 (M+1)+. Step 2: To 40.0 mg (0.057 mmol) (2-(2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine)- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]xin- To a mixture of 1-butyrylamino)ethyl)(methyl)aminecarboxylic acid tert-butyl ester in 1 mL of 1,4-dioxane, 0.5 mL of MeOH was added to obtain a clear solution. 4 M HCl (0.5 mL, 2.0 mmol) in dioxane was added dropwise and the mixture was stirred at room temperature for 30 min. LC-MS showed the reaction was completed. The mixture was concentrated and 5.0 mL of DMF and cesium carbonate were added to the residue. The resulting mixture was stirred at room temperature for 1 hour and concentrated. Crude product by mass induced HPLC (10 to 20% ACN in H2 Purification in O, 3.5 min) then 1 N aqueous HCl was added and lyophilized to give 1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4 -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2 .2] Oct-1-yl)-4-methylpiperazin-2-one (compound No. 108). 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 6.35 (s, 1H), 4.44 (s, 2H), 3.90 (s, 3H), 3.87 (t, J = 5.5 Hz, 2H) , 3.62 (s, 2H), 2.80 (t, J = 5.5 Hz, 2H), 2.45 (m, 5H), 2.17 (dd, J = 7.9, 6.9 Hz, 2H), 2.14 (s, 6H), 2.13 ( s, 3H), 1.80 - 1.73 (m, 6H), 1.50 - 1.43 (m, 6H). MS (ES+): 519.3 (M+1)+. Example 29 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(3-fluoroazetidine Synthesis of -1-yl) acetamidine (Compound No. 133)Step 1: To 16.7 mg (0.120 mmol) of 2-bromoacetic acid and 42.0 mg (0.1 mmol) of 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]xin- HATU (45.6 mg, 0.12 mmol) and DIPEA (25.8 mg, 0.035 mL, 0.2 mmol) were added to a mixture of 1-amine (Compound 1) in DCM (1 mL). The resulting mixture was stirred at room temperature for 1 hour. LC-MS confirmed the completion of the reaction and concentrated the mixture. The crude product was added to a 4 g silica gel column and used to elute from 0 to 50% IPA (containing 0.02 M ammonia) in DCM. The fractions were collected and concentrated to provide 2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)acetamide . RT (Method 1): 1.26 minutes. MS (ES+): 540.2 and 542.1 (M+1)+. Step 2: 27 mg (0.05 mmol) of 2-bromo-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-] at 120 °C under microwave irradiation) b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] Oct-1-yl)acetamide, 7.3 mg (0.065 mmol) 3-fluoroazetidine and a mixture of 20.7 mg (0.15 mmol) of potassium carbonate in EtOAc (1 mL). After concentration, the crude product was subjected to mass-induced HPLC (10 to 30% ACN in H)2 Purification in O, 3.5 min) then 1 N aqueous HCl was added and lyophilized to afford N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4 -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2 .2] Oct-1-yl)-2-(3-fluoroazetidin-1-yl)acetamide (compound No. 133). RT (Method 1): 1.04 minutes. MS (ES+): 535.3 (M+1)+. Example 30 N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-hydroxyacetamide (Compound No. 135) And N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7) -tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(3-hydroxyazetidine- Synthesis of 1-yl) acetamidine (compound No. 136).Step 1: To 10.1 mg (0.11 mmol) 2-sided oxyacetic acid and 42 mg (0.1 mmol) 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] HATU (41.8 mg, 0.11 mmol) and DIPEA (25.8 mg, 0.035 mL, 0.2 mmol) were added as a mixture of oct-1-amine (Compound No. 1) in DCM. The resulting mixture was then stirred at room temperature for 1 hour and then loaded onto a 4 g silica gel column and used to dissolve in 0 to 50% IPA (containing 0.02 M ammonia) in DCM. The fractions were collected and concentrated. The residue was dissolved in 2 mL of DCE, azetidine-3-ol (HCl salt) was added, and the mixture was stirred at room temperature for 30 minutes, and then sodium triethoxy hydride hydride was added. The mixture was then stirred overnight at room temperature. LC-MS showed some desired product 1 but major by-product 2. Massive HPLC by mass induction (10 to 30% ACN in H)2 Purification in O, 3.5 min) then 1 N aqueous HCl was added and lyophilized to give N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine) 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] octyl -1-yl)-2-(3-hydroxyazetidin-1-yl)acetamide (Compound No. 136) [RT (Method 1): 1.05 min. MS (ES+): 478.3 (M+1)+] and N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl) 2-Hydroxyacetamide (Compound No. 135) [RT (Method 1): 0.98 min. MS (ES+): 533.3 (M+1)+], both HCl salts.table 6 : Additional exemplary compounds Administration and pharmaceutical composition For the therapeutic use of the compounds of the invention, such compounds are administered in a therapeutically effective amount, either alone or as part of a pharmaceutical composition. Accordingly, the invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. For the purposes of the present invention, solvates and hydrates are generally considered to be compositions unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical compositions of the present invention may have a unit dose of from about 1 to 1000 mg of the active ingredient for an individual of from about 50 to 70 kg. The therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof will depend on the species, weight, age, and individual condition, disorder, or disease or severity of the individual. A physician, clinician or veterinarian having general skills can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progression of the disorder or disease. The dosage properties cited above can be advantageously demonstrated in vitro and in vivo using mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and preparations. The compounds of the present invention can be administered in vitro in the form of a solution (e.g., an aqueous solution), and enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. The extracorporeal dose can be about 10-3 Moore and 10-9 Molar concentration between. The therapeutically effective amount in vivo may vary from about 0.1 to 500 mg/kg depending on the route of administration. The activity of the compounds according to the invention can be assessed by the following in vitro and in vivo methods. The pharmaceutical compositions of the present invention can be prepared by a method comprising admixing a compound of the present invention or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or excipients. By way of example, the pharmaceutical composition of the present invention is combined with at least one pharmaceutically acceptable carrier in a free form or in a pharmaceutically acceptable salt form by a method of mixing, granulating and/or coating. The agent, diluent or excipient is manufactured. The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising a compound of the invention as an active ingredient, as water promotes degradation of certain compounds. The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low water content ingredients and low moisture or low humidity conditions. Anhydrous pharmaceutical compositions can be prepared and stored such that they retain their anhydrous nature. Thus, anhydrous compositions are packaged using known materials to prevent exposure to water such that they can be included in a suitable defined kit. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs. The invention further provides pharmaceutical compositions and dosage forms comprising one or more agents that reduce the rate of decomposition of a compound of the invention as an active ingredient. Such agents (referred to herein as "stabilizers") include, but are not limited to, antioxidants (such as ascorbic acid), pH buffers or salt buffers, and the like. Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, rectal administration, transdermal administration, parenteral, intravenous administration, intramuscular administration, pulmonary administration, inhalation administration, Intranasal administration, eye administration, and local administration.Oral administration dosage form The pharmaceutical composition of the present invention can be orally administered as a discrete dosage form, including but not limited to capsules, gelatin capsules, capsule tablets, lozenges, chewable tablets, buccal tablets, dispersible powders, granules. , syrup, flavored syrup, solution or suspension in an aqueous or non-aqueous liquid, edible foam or whipped foam and oil-in-water emulsion or water-in-oil emulsion. Thus, for oral administration, a pharmaceutical composition of the invention comprising an effective amount of a compound of the invention may be in solid form (including but not limited to, capsules, gelatin capsules, hard or soft capsules, lozenges, chewable ingots , ingots, capsules, pills, granules or dispersible powders) or in liquid form (including but not limited to solutions, aqueous or oily suspensions, syrups, elixirs, foams, whipped foams or emulsions) production. The pharmaceutical compositions may be subjected to conventional pharmaceutical procedures such as sterilization and/or may contain conventional inert diluents, lubricants or buffers and adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers and buffers. Agent, etc.). Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may comprise a composition selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. One or more of a group of agents to provide a medicinal elegant and palatable preparation. In general, a pharmaceutical composition is a lozenge or gelatin capsule containing the active ingredient and one or more of the following: a) a diluent, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or Glycine; b) a lubricant, for example, cerium oxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; and in the case of a tablet, c) a binder, for example, hydrazine Magnesium aluminate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) disintegrating agents, for example, starch, agar, alginic acid or a sodium salt or an effervescent mixture; and e) an adsorbent, a colorant, a flavoring agent, and a sweetener. Tablets may contain the active ingredient in admixture with non-pharmaceutically pharmaceutically acceptable excipients suitable for the manufacture of lozenges. Such excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example, starch , gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. Tablets may be added as a film coating or an enteric coating according to methods known in the art. Such tablets are provided without the addition of a coating or by the addition of a coating by known techniques to delay decomposition and absorption in the gastrointestinal tract and thereby provide a long lasting effect. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. The formulation for oral use may be presented as a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin) or as a soft gelatin capsule in which the active ingredient is in water Or a mixture of oil media (for example, peanut oil, liquid paraffin or olive oil).Parenteral dosage form In certain embodiments, the pharmaceutical compositions of the invention are administered parenterally by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solution accelerators, salts for regulating osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1 to 75% or from about 1 to 50% of the active ingredient.Topical dosage form In certain embodiments, the pharmaceutical compositions of the present invention are administered topically by a pharmaceutical composition comprising a compound of the present invention in the form of a lotion, gel, ointment, solution, emulsion, suspension or cream. Cast. Compositions suitable for topical administration (e.g., to the skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, for example, for delivery by aerosol or the like. Such topical delivery systems will be specifically adapted for dermal administration, for example, for the treatment of skin cancer, for example, for prophylactic use in sunscreens, lotions, sprays, and the like. They are therefore particularly suitable for use in topical applications, including cosmetics, formulations well known in the art. These may contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives. As used herein, topical administration can also be by inhalation or intranasal administration. They may be in the form of a dry powder from a dry powder inhaler with or without the use of a suitable propellant (alone, as a mixture, for example as a dry blend with lactose, or as a mixed component granule, for example with The phospholipid mixed component granules) are conveniently delivered in the form of an aerosol spray from a pressurized container, pump, spray, atomizer or nebulizer.Rectal administration In certain embodiments, the pharmaceutical compositions of the invention are administered rectally in the form of a suppository, enemas, ointment, cream rectal foam or rectal gel. In certain embodiments, such suppositories are prepared from fatty emulsions or suspensions, cocoa butter or other glycerides.Deposit investment (Depot Administration) In certain embodiments, the pharmaceutical compositions of the invention are formulated as a depot preparation. Such formulations are administered by transplantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, such formulations include polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.Combination therapy The compounds of the invention and the pharmaceutical compositions provided herein are administered alone or in combination with one or more additional therapeutic agents. Combinations of the invention may be administered to a subject having an active ingredient of from about 1 to 1000 mg for an individual of from about 50 to 70 kg. The therapeutically effective dose of such combinations will depend on the species, weight, age, and individual condition of the individual, the disorder or disease in treatment, or the severity thereof. A physician, clinician or veterinarian having general skills can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the progression of the disorder or disease. The dosage properties cited above can be advantageously demonstrated in vitro and in vivo using mammals (e.g., mice, rats, dogs, monkeys) or their isolated organs, tissues, and preparations. The compounds of the present invention can be administered in vitro in the form of a solution (e.g., an aqueous solution), and enterally, parenterally, advantageously intravenously, for example, as a suspension or in an aqueous solution. The extracorporeal dose can be about 10-3 Moore and 10-9 Molar concentration between. The therapeutically effective amount in vivo may vary from about 0.1 to 500 mg/kg depending on the route of administration. The activity of the compounds according to the invention can be assessed by the following in vitro and in vivo methods. The compounds of the invention may be administered simultaneously or before or after with one or more other therapeutic agents. The compounds of the invention may be administered separately by the same or different routes of administration or with other agents presented in the same pharmaceutical composition. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments or nucleic acids that are therapeutically active or enhance therapeutic activity when administered to a patient in combination with a compound of the invention. The present invention provides a pharmaceutical composition comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and other therapeutic agents. The pharmaceutical composition may comprise a pharmaceutically acceptable carrier, as described above, as desired. The present invention provides a product comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and at least one other therapeutic agent as a combined preparation for simultaneous treatment Use separately or sequentially. In one embodiment, the therapeutic pair is by an endosome receptor (eg, TLR7, TLR8, or TLR9), or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7) Treatment of autoimmune diseases or conditions mediated by the activity of /9 and TLR8/9). Products provided as a combined preparation include other therapeutic agents comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and together in the same pharmaceutical composition, Or a combination of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and other therapeutic agents in a separate form (eg, in the form of a kit) . In one embodiment, the invention provides a product comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and at least one other therapeutic agent as a combined preparation For simultaneous, separate or sequential use in therapy. In one embodiment, the treatment is treatment of an autoimmune disease or condition mediated by TLR7, TLR7 and TLR8 or TLR7, TLR8 and TLR9 activity. Products provided as a combined preparation include other therapeutic agents comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and together in the same pharmaceutical composition or A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and other therapeutic agents in a separate form (e.g., in the form of a kit). The present invention provides a product comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and at least one other therapeutic agent as a combined preparation for simultaneous treatment Use separately or sequentially. In one embodiment, the treatment is treatment of an autoimmune disease or condition mediated by the activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof. Products provided as a combined preparation include other therapeutic agents comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and together in the same pharmaceutical composition or A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) and other therapeutic agents in a separate form (e.g., in the form of a kit). In one embodiment, the invention provides a kit comprising two or more different pharmaceutical compositions, at least one of the different pharmaceutical compositions comprising formula (A), formula (I), formula (II), A compound of the formula (Ia to Ip) or a formula (IIa to IIk). In one embodiment, the kit includes means for retaining the compositions, such as a container, a separate bottle, or a separate foil package. Examples of such kits are blister packs, such as those commonly used in tablets, capsules and the like. The kit of the invention can be used to administer different dosage forms (e.g., oral and parenteral) for administering the individual compositions at different dosage intervals or for titrating the respective compositions relative to one another. To aid compliance, the kits of the present invention typically include instructions for administration. In the combination therapies of the invention, the compounds of the invention and the other therapeutic agents may be made and/or formulated by the same or different manufacturers. Furthermore, the compounds of the invention and other therapeutic agents may be used together in combination therapy: (i) prior to release of the combination product to a physician (eg, in the case of a kit comprising a compound of the invention and other therapeutic agents); Ii) by the physician himself (or under the direction of a physician) immediately prior to administration; (iii) by the patient himself, for example, during the sequential administration of the compounds of the invention and other therapeutic agents. In certain embodiments of the combination therapies described herein, the compounds of the invention and additional formulations additionally function. In certain embodiments of the combination therapies described herein, the compounds of the invention and additional therapeutic agents act synergistically. Additional therapeutic agents for use in combination with the compounds of the invention include, but are not limited to, anti-inflammatory agents, immunomodulators, immunosuppressive agents, interleukins, non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial compounds, anti-rheumatic compounds , an inhibitor of B cell activating factor (BAFF), an inhibitor of B lymphocyte stimulator (BLyS), and a steroid hormone. Non-steroidal anti-inflammatory drugs (NSAIDs) for use in combination with the compounds of the invention include, but are not limited to, salicylic acid, acetaminosalicylic acid, methyl salicylate, diflunisal, salicylate , olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, methoxy Mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen ), naproxen sodium, fenoprofen, ketoprofen, flurbinprofen, oxaprozin oxaprozin, piroxicam, merlot Meloxicam, ampiroxicam, droxicam, piroxicam, tenoxicam, nabumetome, phenylbutazone Phenylbutazone), oxyphenbutazone, antipyrine, aminopyrine, apocytone (apa) Zone) and nimesulide. Anti-rheumatic compounds for use in combination with the compounds of the invention include, but are not limited to, amine formazan. Antimalarial compounds for use in combination with the compounds of the invention include, but are not limited to, chloroquine and hydroxychloroquine. Inhibitors of B cell activating factor (BAFF) used in combination with the compounds of the invention are also known as inhibitors of B lymphocyte stimulator (BLyS), including but not limited to benzumab (Benlysta®), Blisibimod And BR3-Fc. Immunosuppressive agents for use in combination with the compounds of the invention include, but are not limited to, mycophenolate mofetil (MMF), mycophenolic acid, cyclophosphamide, azathioprine, and laquinimod ( 5-Chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide). Steroid hormones for use in combination with the compounds of the invention include, but are not limited to, dehydroepiandrosterone (DHEA). Certain aspects of the pharmaceutical compositions and combinations of the present invention are provided in the following list of additional enumerated embodiments. Features specified in the various embodiments may be combined with other specified features to provide further embodiments of the invention. Embodiment 93: A pharmaceutical composition comprising a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof and a medicament An acceptable carrier. Embodiment 94: A pharmaceutical composition comprising a compound of Formula (I) or Formula (Ia to Ip), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 95: A pharmaceutical composition comprising a compound of formula (II) or formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 96: A pharmaceutical composition comprising a compound of formula (A), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 97: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable compound thereof Salt and pharmaceutically acceptable carrier. Embodiment 98: A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or Formula (Ia to Ip), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 99: A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (II) or Formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 100: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (A), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 101: The pharmaceutical composition of the present invention further comprises one or more independently selected from the group consisting of an anti-inflammatory agent, an immunomodulator, an immunosuppressive agent, an interleukin, a non-steroidal anti-inflammatory drug (NSAID), an antimalarial compound, and an antirheumatic agent. A compound, an inhibitor of B cell activating factor (BAFF), an inhibitor of B lymphocyte stimulator (BLyS), and an additional therapeutic agent for steroid hormones. Embodiment 102: A combination comprising a therapeutically effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof And one or more additional therapeutic agents and, if desired, further comprising a pharmaceutically acceptable carrier, wherein the additional therapeutic agent is independently selected from the group consisting of an anti-inflammatory agent, an immunomodulator, an immunosuppressive agent, an interleukin, a non-steroid Anti-inflammatory drugs (NSAID), anti-malarial compounds, anti-rheumatic compounds, inhibitors of B cell activating factor (BAFF), inhibitors of B lymphocyte stimulator (BLyS), and steroid hormones.Pharmacology and utility The compounds of the invention are generally endosomal steroid receptors (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/ 9) an inhibitor, and thus may be suitable for treatment with an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, Autoimmune diseases associated with the activity of TLR7/9 and TLR8/9). Thus, the compounds of the invention are useful in the treatment of autoimmune diseases, including systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura Suppurative sweat glands, dermatomyositis, polymyositis, Sjögren's syndrome, arthritis, rheumatoid arthritis or psoriasis. The compounds of the invention are generally inhibitors of TLR7, TLR7 and TLR8 or TLR7 and TLR8 and TLR9 and are therefore useful for the treatment of autoimmune diseases associated with TLR7 activity, TLR7 and TLR8 activity or TLR7 and TLR8 and TLR9 activity. Thus, the compounds of the invention are useful in the treatment of autoimmune diseases, including systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura Suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In addition, the compounds of the invention are generally inhibitors of the endogenous steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof, and are therefore useful for the treatment of receptors with intracellular steroid receptors (eg, Autoimmune disease associated with the activity of the TLR7, TLR8 or TLR9) pathway or any combination thereof. Thus, the compounds of the invention are useful in the treatment of autoimmune diseases, including systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura Suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. A compound of the invention in free form or in the form of a pharmaceutically acceptable salt exhibits valuable pharmacological properties, for example, as indicated herein, as indicated in vitro and in vivo, and thus indicated for use in therapy or Research chemicals, for example, as a tool compound. Accordingly, as another embodiment, the invention provides the use of a compound of the invention in therapy, wherein the treatment is treatment of an autoimmune disease, which can be by an intracellular steroid receptor (eg, Treatment with TLR7, TLR8 or TLR9) or any combination thereof, including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the treatment is treatment with an autoimmune disease that can be treated by inhibition of TLR7, TLR7 and TLR8 or TLR7 and TLR8 and TLR9. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the invention provides the use of a compound of the invention in therapy, wherein the treatment is treatment of an autoimmune disease, which is by intracellular receptors (eg, TLR7, TLR8) Treatment with either TLR9) pathway and any combination thereof. In another embodiment, the autoimmune disease is selected from the group consisting of, for example, systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppuration Autoimmune disease of sweat glands, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the invention provides a method of treating an autoimmune disease by an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) or any combination thereof (including The treatment is not limited to the inhibition of TLR7/8, TLR7/8/9, TLR7/9 and TLR8/9), wherein the method comprises administering a therapeutically acceptable amount of formula (A), formula (I), (II), a compound of the formula (Ia to Ip) or a formula (IIa to IIk). In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the invention provides a method of treating an autoimmune disease, the autoimmune disease being treated by inhibition of TLR7, TLR7 and TLR8 or TLR7 and TLR8 and TLR9, wherein the method comprises administering a therapeutic Acceptable amounts are compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk). In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the invention provides a method of treating an autoimmune disease by inhibition of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof Treatment, wherein the method comprises administering a therapeutically acceptable amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk). In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Thus, as another embodiment, the present invention provides compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) for use in the manufacture of therapeutic and intracellular bodies Autoimmune disease associated with the activity of a purinoceptor (eg, TLR7, TLR8, or TLR9) or any combination thereof, including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9 The use of the medicament. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. In another embodiment, the invention provides compounds of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) for use in the treatment of TLR7, TLR7 and TLR8 Or the use of an agent for autoimmune diseases associated with the activity of TLR7 and TLR8 and TLR9. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. As another example, the present invention provides a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) for use in the treatment of intracellular Use of a body (e.g., TLR7, TLR8 or TLR9) pathway or an agent of any combination of activities associated with an autoimmune disease. In another embodiment, the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation , dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. The use of the compounds of the invention and certain aspects of the methods of treatment of the invention are provided in the following list of additional enumerated examples. Features specified in the various embodiments may be combined with other specified features to provide further embodiments of the invention. Example 103: One for treatment with an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9 and A method of autoimmune disease associated with the activity of TLR8/9), wherein the method comprises administering to the individual in need of such treatment an effective amount of formula (A), formula (I), formula (II), formula (Ia) To the Ip) or the compound of the formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, whereby the disease is treated. Example 104: One for treatment with an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9 and A method of autoimmune associated with the activity of TLR8/9), wherein the method comprises administering to an individual in need of such treatment an effective amount of formula (A), formula (I), formula (II), formula (Ia to Ip) or a compound of the formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, and the autoimmune disease thereof, systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary Cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Embodiment 105: A method for treating an autoimmune disease associated with activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof, wherein the method comprises administering to the treatment The individual in need thereof is administered an effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, whereby the agent is treated disease. Embodiment 106: A method for treating an autoimmune disease associated with activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof, wherein the method comprises treating The individual in need thereof is administered an effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, and wherein Systemic immune system systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, rest Glen syndrome, arthritis, rheumatoid arthritis or psoriasis. Example 107: A method for treating an autoimmune disease associated with i) TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity, wherein the method comprises An individual having such a therapeutic need to administer an effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, This treats the disease. Example 108: A method for treating an autoimmune disease associated with i) TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity, wherein the method comprises An individual having such a therapeutic need to administer an effective amount of a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, and The autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, and more Myositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Embodiment 109: A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in therapy and intracellular Autoimmune association of a steroid receptor (eg, TLR7, TLR8, or TLR9) or any combination thereof, including but not limited to TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9 Disease 110. A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in therapy and The activity of an endosome receptor (eg, TLR7, TLR8, or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) is associated with Autoimmune disease, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, Dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Example 111: a formula (A), formula (I), formula (II), formula (Ia to Ip) Or a compound of the formula (IIa to IIk) or A pharmaceutically acceptable salt for use in the treatment of an autoimmune disease associated with the activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof. Example 112: One Formula ( A), a compound of formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, for use in the treatment of receptors with intracellular receptors (eg An autoimmune disease associated with the activity of a TLR7, TLR8 or TLR9) pathway, or any combination thereof, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary Biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Example 113: A formula (A) a compound of formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease associated with i) TLR7 Activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity, wherein the autologous The disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, rest Glen syndrome, arthritis, rheumatoid arthritis or psoriasis. Embodiment 114: A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in therapy and intracellular Autoimmune association of a steroid receptor (eg, TLR7, TLR8, or TLR9) or any combination thereof, including but not limited to TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9 Disease: Example 115: a compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in therapy and The activity of an endosome receptor (eg, TLR7, TLR8, or TLR9) or any combination thereof (including but not limited to, TLR7/8, TLR7/8/9, TLR7/9, and TLR8/9) is associated with Autoimmune disease, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, Dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Example 116: a formula (A), formula (I), formula (II), formula (Ia to Ip) Or a compound of the formula (IIa to IIk) or A pharmaceutically acceptable salt for use in the treatment of an autoimmune disease associated with the activity of an intracellular steroid receptor (eg, TLR7, TLR8 or TLR9) pathway, or any combination thereof. Example 117: One Formula ( A), a compound of formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, for use in the treatment of receptors with intracellular receptors (eg An autoimmune disease associated with the activity of a TLR7, TLR8 or TLR9) pathway, or any combination thereof, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary Biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. Example 114: A formula (A) a compound of formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with i) TLR7 activity, or ii TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity, wherein the disease is autoimmune Disease. Embodiment 115: A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof, for use in the manufacture thereof for treatment with TLR7 Use of an active, TLR7 and TLR8 activity or an agent for an autoimmune disease associated with TLR7 and TLR8 and TLR9 activity. Embodiment 116: A compound of formula (A), formula (I), formula (II), formula (Ia to Ip) or formula (IIa to IIk) or a pharmaceutically acceptable salt thereof for use in the manufacture of a therapeutic autoimmune The use of a medicament for diseases, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland Inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis.analysis The compounds of the invention were analyzed in the assays described in the following paragraphs.Test compound preparation Compounds are typically serially diluted (1/3) in DMSO and plated on sterile 384-well tissue culture dishes and stored until ready for use. Each ten point dilution is usually inoculated in parallel in triplicate.In humans PBMC In the middle TLR7 , TLR8 and TLR9 Antagonist analysis PBMC Separation On the morning of the analysis, fresh blood was collected from the normal donor to the heparinized syringe with written informed consent. The blood was diluted in RPMI-1640 medium and white blood cells were isolated from red blood cells by centrifugation (800 g 15' 0 acceleration, 0 brake) on a Ficoll pad. Peripheral blood mononuclear cells (PBMC) were isolated from platelets by low-speed centrifugation (1000 RPM 10') in a series of PBS + 5% HI-FBS and 1 mm EDTA. Purified PBMC were resuspended in assay medium (RPMI-1640 w Glutamax (Invitrogen) supplemented with 5% HI-FBS, 10 mm HEPES, 50 μM β-mercaptoethanol and 100 mG/L penicillin/streptomycin mixture) in. Live PBMC were counted on a hemocytometer and kept on ice until ready for vaccination.Agonist treatment batch transfection TLR7/8 agonist ssRNA40 (IDT) at 4X concentration (for TLR8 or TLR7 analysis, 4 μg/ml or 40 μg/ml, respectively) was combined with 10% DOTAP (Roche) for 30 minutes in assay medium and then added to PBMC suspension (5 million cells/ml). After addition, the final concentration of ssRNA40 in the TLR7/8 stimulated PBMC suspension was 1 μg/ml for the TLR8 assay and 10 μg/mL for the TLR7 assay. The final DOTAP concentration was 2.5%. The diluted PBMC (5 million cells/ml) was treated with 4X TLR9 agonist ODN2216 (Invivogen). The final concentration of ODN2216 in the TLR9 stimulated PBMC suspension was 0.3 μm.PBMC Inoculation and compound treatment The agonist-stimulated PBMCs were seeded on compound treated 384 well plates at 150,000 cells/well. Unstimulated PBMC were inoculated on each plate as a control. The inoculation volume was 40 μL per well. The concentration of DMSO in each well was 0.25%. Each assay included a compound-free individual disk with titrations of ssRNA40 and ODN2216 to measure the agonist response of each donor PBMC formulation. Place the assay disk in a tissue culture incubator (37 ° C, 5% CO)2 Place in 14 to 16 hours. After the incubation, the plates were centrifuged and stored at -20 ° C until they were analyzed.For TLR8 Active IL-6 TR-FRET analysis: 1) Use Cisbio Human IL-6 kit, 20,000 tests (62 TNFPEC), and GNF High-Base TC 384 well plate (cat # 789163G); 2) Anti-TIL-6 cryptate compound and anti-IL -6 XL665 conjugate 1:20 diluted in rehydration buffer; 3) Preparation of 3 μL/well anti-IL-6 cryptate conjugate and 3 μL/well anti-IL-6 XL665 conjugate Mixture; 4) Add 6 μL/well HTRF dilution master mix (mastermix) to 6 μL of the supernatant supernatant sample in a shallow microporous disk (proxiplate); 5) at room temperature in the dark Plate culture for 3 hours; and 6) IL-6 production was performed using an HTRF setting and a proportional reading: (XL665 emission/Eu cryptate emission) X10,000 Envision disk reader (665 nm (emission) / 590 nm (excitation)) Measurements were taken.For TLR7 or TLR9 Active IFN α 2b AlphaLISA analysis After thawing the assay plate, 6 μL of the supernatant sample was transferred to a low volume AlphaPlate 384SW (Perkin-Elmer). The concentration of IFNα in the supernatant is IFNα2b AlphaLISA analysis (Perkin-Elmer: AL297F) was performed. First, 3 μL of IFNα receptor beads/biotinylated antibody solution was added using a laboratory automated device. After one hour of incubation, 3 μL of streptavidin receptor bead solution was added. Plates containing this mixture were incubated for one hour in the dark and read on a suitable disk reader under reading parameters set by the manufacturer. (Envision, EnSpire: Perkin-Elmer).THP-1 TLR8 Antagonist TNF αTR-FRET analysis Cell-based analysis: 1) THP-1 cells were cultured in RPMI 1640 with 10% FBS, 10 mm HEPES, 1 mm sodium pyruvate, 1% penicillin-streptomycin L-glutamic acid and 1% non-essential amino acid; 2) Three different passages of THP-1 cells in the assay medium were pooled, counted and resuspended in medium with the same culture medium but with 5% FBS; 3) Dilute the cells to 100,000 cells/well ( 30 μL/well) and dilute the R848 agonist to 25 μm in culture medium at 10 μl/well; 4) Dilute the combined cells and agonist and add to the test compound containing DMSO in 40 μL/well. Greiner assay plate, the test compound was pre-spotted at a maximum dose of 8 mM and a 1:3 serial dilution of -10 μm and a final maximum dose of 50 nL per well; 5) at 37 ° C 5% CO2 The plates were incubated overnight for 18 to 20 hours; 6) the plates were then centrifuged at 1000 rpm for 2 minutes at room temperature; 7) 10 μL/well supernatant was transferred to 384 well low volume white Grenay shallow well microplates; and 8) TNFα concentrations were measured using the TR-FRET assay described below.TNF α TR-FRET analysis: 1) Using the Cisbio Human TNFα kit, 20,000 tests (62 TNFPEC) and Grena Bio-One LIA-white TC 384-well small volume plate (cat # 784080); 2) Anti-TNFα cryptate compound conjugate and anti- TNFα XL665 conjugate diluted 1:20 in rehydration buffer; 3) Preparation of a 5 μL/well anti-TNFα cryptate conjugate and a 1:1 mixture of 5 μL/well anti-TNFα XL665 conjugate; 4) 10 μL/well HTRF diluted master mix was added to 10 μL of the supernatant supernatant sample in a shallow well microplate; 5) the plates were incubated for 3 hours at room temperature in the dark; and 6) TNFα production Concentrations were measured using an Envision disk reader (665 nm (emission) / 590 nm (excitation)). The various compounds of the invention in free form or in the form of a pharmaceutically acceptable salt exhibit, for example, pharmacological properties as indicated by the results of the analysis presented in Table 7. IC50 The value is given as the concentration of the reaction between the baseline and the maximum reaction of the test compound in question. The dotted line (---) in Table 7 means that no test was performed.table 7 : Analysis results table 8 : Analysis results It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications and changes may be made by those skilled in the art and are intended to be included within the spirit and scope of the present application. Within the scope of the patent application.

Claims (21)

一種具有式(A)結構之化合物或其醫藥上可接受之鹽：式(A) 其中， RA 係、、、、、、、、、或； L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -、-XCH2 -或-CH2 X-； X係-CH2 -或O； R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、 -NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)(CH2 )n R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 、-NHC(=O)(CH2 )n NR9 S(=O)2 R5 、、、8-氧雜-3-氮雜雙環[3.2.1]辛基、具有獨立地選自N、O及S之1至3個環成員之5至6員雜芳基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R7 基團取代； R2 係H、C1 -C6 烷基、C1 -C6 鹵烷基或經1至2個R15 基團取代之C1 -C6 烷基； R3 係H、C1 -C6 烷基、-CD3 或經1至2個R10 基團取代之苄基； R4 係H、NH2 、C1 -C6 烷基、鹵基或經0至2個R18 基團取代之苯基； 各R5 係獨立地選自C1 -C6 烷基、-CD3 及-(CH2 )n OR9 ； R6 係C3 -C6 環烷基、氧雜-3-氮雜雙環[3.2.1]辛烷或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R7 係獨立地選自C1 -C6 烷基、鹵基、羥基、側氧基及經1至3個-OH取代之C1 -C6 烷基； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R10 係C1 -C6 烷氧基或C3 -C6 環烷基； R11 係未經取代或經1至3個C1 -C6 烷基取代之C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； R15 係-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CHR9 )n R6 、-NHC(=O)(CHR9 )n N(R8 )2 、-NHC(=O)(CHR9 )n NHR8 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR8 、-N(R6 R8 )、-NH(C(R9 )2 )n R10 、-NR9 C(=O)OR11 、-NH(CHR9 )n R6 、-N(R6 )2 、-N(CD3 )2 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 ； 各R16 係C1 -C6 烷基； 各R17 係獨立地選自H及C1 -C6 烷基； 各R18 係獨立地選自鹵基、-CN、C1 -C6 烷氧基及C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。A compound having the structure of formula (A) or a pharmaceutically acceptable salt thereof: Formula (A) where R A is , , , , , , , , , or ; L system -CH 2 - or -CH 2 CH 2 -; Y 1 system -CH 2 - or -CH 2 CH 2 -; Y 2 system -CH 2 - or -CH 2 CH 2 -; Y 3 system -CH 2 -, -XCH 2 - or -CH 2 X-; X--CH 2 - or O; R 1 -NHC(=O)R 6 , -NHC(=O)(CH 2 ) n R 6 ,- NH(CH 2 ) n C(=O)R 6 , -NHC(=O)(CH 2 ) m NHR 5 , -NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(= O)(CHR 9 ) m NHR 5 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CH 2 ) n OR 9 , -NHC(=O)OR 9 , -NH( CH 2 ) m C(=O)N(R 5 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , NHC(=O)(CHR 9 ) n R 6 , -NHC(=O) (CHR 9 ) n N(R 8 ) 2 , -NHC(=O)(CHR 9 ) n NHR 8 , -NH(CHR 9 ) n C(=O)N(R 8 ) 2 , -NH(CHR 9 m C(=O)R 6 , -NHR 6 , -NR 5 R 6 , -NH 2 , -N(R 5 ) 2 , -NHR 5 , -NHR 8 , -N(R 6 R 8 ), - NH(C(R 9 ) 2 ) n R 10 , -NR 9 C(=O)OR 11 , -NH(CH 2 ) n R 6 , -NH(CHR 9 ) n R 6 , -N(R 6 ) 2 , -NHC(=O)(CH 2 ) n N(CD 3 ) 2 , -NH(CHR 9 ) n CH 2 OR 9 , -NHCH 2 (CHR 9 ) n OR 9 , -NH(CHR 9 ) n OR 9 , -NR 9 (CH 2 ) n OR 9 , -NHCH 2 (C(R 9 ) 2 ) n OR 9 , -OR 9 , -NR 9 C(=O)R 5 , -NR 9 C(= O) (CH 2) n R 5, -NR 9 C (= O) OR 5 -NHS (= O) 2 R 5 , -NHC (= O) (CH 2) n NR 9 C (= O) R 5, -NHC (= O) (CH 2) n NR 9 S (= O) 2 R 5 , , , 8-oxa-3-azabicyclo[3.2.1]octyl, 5 to 6 membered heteroaryl having 1 to 3 ring members independently selected from N, O and S or independently selected from 4 to 6 membered heterocycloalkyl of 1 to 2 ring members of N, NH, NR 16 and O, which are unsubstituted or substituted with 1 to 2 R 7 groups; R 2 is H, C 1 - C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkyl substituted with 1 to 2 R 15 groups; R 3 H, C 1 -C 6 alkyl, -CD 3 or a benzyl group substituted with 1 to 2 R 10 groups; R 4 is H, NH 2 , C 1 -C 6 alkyl, halo or phenyl substituted with 0 to 2 R 18 groups; each R 5 Is independently selected from C 1 -C 6 alkyl, -CD 3 and -(CH 2 ) n OR 9 ; R 6 is C 3 -C 6 cycloalkyl, oxa-3-azabicyclo[3.2.1 An octane or a 4 to 6 membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH, NR 16 and O, which are unsubstituted or substituted with 1 to 2 R 12 groups Each R 7 is independently selected from C 1 -C 6 alkyl, halo, hydroxy, pendant oxy and C 1 -C 6 alkyl substituted with 1 to 3 -OH; each R 8 is independently selected From C 1 -C 6 haloalkyl, -(C(R 9 ) 2 ) n OR 9 and C 1 -C 6 alkyl substituted by 1 to 3 -OH; each R 9 Is independently selected from H and C 1 -C 6 alkyl; R 10 is C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl; R 11 is unsubstituted or 1 to 3 C 1 -C 6 alkyl substituted C 3 -C 6 cycloalkyl; each R 12 is independently selected from C 1 -C 6 alkyl, hydroxy, halo and C 1 -C substituted with 1 to 3 -OH 6 alkyl; R 13 H or C 1 -C 6 alkyl; R 14 H or C 1 -C 6 alkyl; R 15 -NHC(=O)(CH 2 ) m NHR 5 , -NHC ( =O)(CH 2 ) m N(R 5 ) 2 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CHR 9 ) n R 6 , -NHC(=O)( CHR 9 ) n N(R 8 ) 2 , -NHC(=O)(CHR 9 ) n NHR 8 , -NH(CHR 9 ) n C(=O)N(R 8 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , -NHR 6 , -NH 2 , -N(R 5 ) 2 , -NHR 8 , -N(R 6 R 8 ), -NH(C(R 9 ) 2 ) n R 10 , -NR 9 C(=O)OR 11 , -NH(CHR 9 ) n R 6 , -N(R 6 ) 2 , -N(CD 3 ) 2 , -NH(CHR 9 ) n OR 9 or - NHCH 2 (C(R 9 ) 2 ) n OR 9 ; each R 16 is C 1 -C 6 alkyl; each R 17 is independently selected from H and C 1 -C 6 alkyl; each R 18 is independently Selected from halo, -CN, C 1 -C 6 alkoxy and C 1 -C 6 alkyl; m series 1, 2, 3, 4, 5 or 6, and n series 1, 2, 3, 4, 5 or 6. 如請求項1之化合物，其具有式(I)或式(II)結構，或其醫藥上可接受之鹽： 式(I) 式(II)， 其中Y1 、Y2 、Y3 、L、R1 、R2 及RA 係如請求項1中定義。The compound of claim 1, which has the structure of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof: Formula (I) Formula (II), wherein Y 1 , Y 2 , Y 3 , L, R 1 , R 2 and R A are as defined in claim 1. 如請求項1或請求項2之化合物，其中式(A)化合物或式(I)化合物具有式(Ia)、式(Ib)、式(Ic)、式(Id)、式(Ie)、式(If)、式(Ig)、式(Ih)、式(Ii)、式(Ij)或式(Ik)之結構，或其醫藥上可接受之鹽：、、 式(Ia) 式(Ib)、式(Ic) 式(Id)、式(Ie) 式(If)、式(Ig) 式(Ih)、式(Ii) 式(Ij)， 式(Ik) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 及R14 係如請求項1中定義。The compound of claim 1 or claim 2, wherein the compound of formula (A) or the compound of formula (I) has formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula The structure of (If), formula (Ig), formula (Ih), formula (Ii), formula (Ij) or formula (Ik), or a pharmaceutically acceptable salt thereof: , , formula (Ia), formula (Ib) , Formula (Ic) (Id) , Formula (Ie) (If) , Formula (Ig) (Ih) , Formula (Ii) (Ij) Formula (Ik) wherein Y 1 , Y 2 , Y 3 , L, R 1 , R 2 , R 3 , R 4 , R 13 and R 14 are as defined in Claim 1. 如請求項1或請求項2之化合物，其中式(A)化合物或式(II)化合物具有式(IIa)、式(IIb)、式(IIc)、式(IId)、式(IIe)、式(IIf)、式(IIg)、式(IIh)、式(IIi)、式(IIj)或式(IIk)之結構，或其醫藥上可接受之鹽：、、 式(IIa) 式(IIb)、式(IIc) 式(IId)、式(IIe) 式(IIf)、式(IIg) 式(IIh)、式(IIi) 式(IIj)， 式(IIk) 其中Y1 、Y2 、Y3 、L、R1 、R2 、R3 、R4 、R13 及R14 係如請求項1中定義。The compound of claim 1 or claim 2, wherein the compound of formula (A) or the compound of formula (II) has formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIe), formula The structure of (IIf), formula (IIg), formula (IIh), formula (IIi), formula (IIj) or formula (IIk), or a pharmaceutically acceptable salt thereof: , , formula (IIa), formula (IIb) , Formula (IIc) (IId) , Formula (IIe) (IIf) , Formula (IIg) (IIh) , Formula (IIi) (IIj) Wherein Y 1 , Y 2 , Y 3 , L, R 1 , R 2 , R 3 , R 4 , R 13 and R 14 are as defined in claim 1. 如請求項1或請求項2之化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NHC(=O)(CH2 )n OR9 、 -NHC(=O)OR9 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )m C(=O)R6 、-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NR9 C(=O)OR11 、-NH(CH2 )n R6 、-N(R6 )2 、-NHC(=O)(CH2 )n N(CD3 )2 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 、-NHCH2 (C(R9 )2 )n OR9 、-OR9 、-NR9 C(=O)R5 、-NR9 C(=O)OR5 、-NHS(=O)2 R5 、-NHC(=O)(CH2 )n NR9 C(=O)R5 或-NHC(=O)(CH2 )n NR9 S(=O)2 R5 。The compound of claim 1 or claim 2, wherein R 1 is -NHC(=O)R 6 , -NHC(=O)(CH 2 ) n R 6 , -NH(CH 2 ) n C(=O R 6 , -NHC(=O)(CH 2 ) m NHR 5 , -NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(=O)(CHR 9 ) m NHR 5 , -NHC(=O)(CH 2 ) m NH 2 , -NHC(=O)(CH 2 ) n OR 9 , -NHC(=O)OR 9 , -NH(CH 2 ) m C(=O)N (R 5 ) 2 , -NH(CHR 9 ) m C(=O)R 6 , -NHR 6 , -NR 5 R 6 , -NH 2 , -N(R 5 ) 2 , -NHR 5 , -NHR 8 , -NR 9 C(=O)OR 11 , -NH(CH 2 ) n R 6 , -N(R 6 ) 2 , -NHC(=O)(CH 2 ) n N(CD 3 ) 2 , -NH (CHR 9 ) n CH 2 OR 9 , -NHCH 2 (CHR 9 ) n OR 9 , -NH(CHR 9 ) n OR 9 , -NR 9 (CH 2 ) n OR 9 , -NHCH 2 (C(R 9 ) 2) n OR 9, -OR 9, -NR 9 C (= O) R 5, -NR 9 C (= O) OR 5, -NHS (= O) 2 R 5, -NHC (= O) ( CH 2 ) n NR 9 C(=O)R 5 or -NHC(=O)(CH 2 ) n NR 9 S(=O) 2 R 5 . 如請求項1或請求項2之化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CH2 )n R6 、-NH(CH2 )n C(=O)R6 、-NHC(=O)(CH2 )m NHR5 、-NHC(=O)(CH2 )m N(R5 )2 、-NHC(=O)(CHR9 )m NHR5 、-NHC(=O)(CH2 )m NH2 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NHR6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-NH(CHR9 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 。The compound of claim 1 or claim 2, wherein R 1 is -NHC(=O)R 6 , -NHC(=O)(CH 2 ) n R 6 , -NH(CH 2 ) n C(=O R 6 , -NHC(=O)(CH 2 ) m NHR 5 , -NHC(=O)(CH 2 ) m N(R 5 ) 2 , -NHC(=O)(CHR 9 ) m NHR 5 , -NHC(=O)(CH 2 ) m NH 2 , -NH(CH 2 ) m C(=O)N(R 5 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , -NHR 6 — —NH 2 , —N(R 5 ) 2 , —NHR 5 , —NHR 8 , —NH(CHR 9 ) n OR 9 or —NHCH 2 (C(R 9 ) 2 ) n OR 9 . 如請求項1或請求項2之化合物，其中， R1 係-NHC(=O)R6 、-NHC(=O)(CHR9 )n R6 、-NH(CHR9 )n C(=O)R6 或-NHR6 。The compound of claim 1 or claim 2, wherein R 1 is -NHC(=O)R 6 , -NHC(=O)(CHR 9 ) n R 6 , -NH(CHR 9 ) n C(=O ) R 6 or -NHR 6 . 如請求項1或請求項2之化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係-NH(CH2 )n C(=O)R6 、-NH(CH2 )m C(=O)N(R5 )2 、-NH(CHR9 )n C(=O)R6 、-NH(CHR9 )n C(=O)N(R8 )2 、-NH(CHR9 )m C(=O)R6 、-NH(C(R9 )2 )n R10 、-NH(CH2 )n R6 、-NH(CHR9 )n R6 、-NH(CHR9 )n CH2 OR9 、-NHCH2 (CHR9 )n OR9 、-NH(CHR9 )n OR9 、-NR9 (CH2 )n OR9 或-NHCH2 (C(R9 )2 )n OR9 ； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R5 獨立地係C1 -C6 烷基、-CD3 或-(CH2 )n OR9 ； R6 係C3 -C6 環烷基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R9 係獨立地選自H及C1 -C6 烷基； R10 係C1 -C6 烷氧基或C3 -C6 環烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 獨立地係H或C1 -C6 烷基； 各R18 獨立地係鹵基、-CN、C1 -C6 烷氧基或C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。The compound of claim 1 or claim 2, wherein L is -CH 2 - or -CH 2 CH 2 -; Y 1 is -CH 2 - or -CH 2 CH 2 -; Y 2 is -CH 2 - or -CH 2 CH 2 -; Y 3 -CH 2 - or -XCH 2 -; X--CH 2 - or O; R 1 -NH(CH 2 ) n C(=O)R 6 , -NH( CH 2 ) m C(=O)N(R 5 ) 2 , -NH(CHR 9 ) n C(=O)R 6 , -NH(CHR 9 ) n C(=O)N(R 8 ) 2 , -NH(CHR 9 ) m C(=O)R 6 , -NH(C(R 9 ) 2 ) n R 10 , -NH(CH 2 ) n R 6 , -NH(CHR 9 ) n R 6 ,- NH(CHR 9 ) n CH 2 OR 9 , -NHCH 2 (CHR 9 ) n OR 9 , -NH(CHR 9 ) n OR 9 , -NR 9 (CH 2 ) n OR 9 or -NHCH 2 (C(R 9 ) 2 ) n OR 9 ; R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; R 3 is H, C 1 -C 6 alkyl or -CD 3 ; R 4 H, NH 2 , C 1 -C 6 alkyl or halo; each R 5 is independently C 1 -C 6 alkyl, -CD 3 or -(CH 2 ) n OR 9 ; R 6 C 3 -C a 6- cycloalkyl group or a 4- to 6-membered heterocycloalkyl group having 1 to 2 ring members independently selected from N, NH, NR 16 and O, which are unsubstituted or have 1 to 2 R 12 groups Substituent; each R 8 is independently selected from C 1 -C 6 haloalkyl, -(C(R 9 ) 2 ) n OR 9 and C 1 -C 6 alkyl substituted with 1 to 3 -OH; Each R 9 system is independently selected from H and C 1 -C 6 alkyl; R 10 is C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl; each R 12 is independently selected from C 1 - C 6 alkyl, hydroxy, halo and C 1 -C 6 alkyl substituted by 1 to 3 -OH; R 13 H or C 1 -C 6 alkyl; R 14 H or C 1 -C 6 Alkyl; each R 16 is C 1 -C 6 alkyl; each R 17 is independently H or C 1 -C 6 alkyl; each R 18 is independently halo, -CN, C 1 -C 6 alkoxy Or a C 1 -C 6 alkyl group; m system 1, 2, 3, 4, 5 or 6, and n system 1, 2, 3, 4, 5 or 6. 如請求項1或請求項2之化合物，其中， L係-CH2 -或-CH2 CH2 -； Y1 係-CH2 -或-CH2 CH2 -； Y2 係-CH2 -或-CH2 CH2 -； Y3 係-CH2 -或-XCH2 -； X係-CH2 -或O； R1 係-NHR6 、-NR5 R6 、-NH2 、-N(R5 )2 、-NHR5 、-NHR8 、-N(R6 R8 )或-N(R6 )2 ； R2 係H、C1 -C6 烷基或C1 -C6 鹵烷基； R3 係H、C1 -C6 烷基或-CD3 ； R4 係H、NH2 、C1 -C6 烷基或鹵基； 各R5 獨立地係C1 -C6 烷基、-CD3 或-(CH2 )n OR9 ； R6 係C3 -C6 環烷基或具有獨立地選自N、NH、NR16 及O之1至2個環成員之4至6員雜環烷基，其係未經取代或經1至2個R12 基團取代； 各R8 係獨立地選自C1 -C6 鹵烷基、-(C(R9 )2 )n OR9 及經1至3個-OH取代之C1 -C6 烷基； 各R12 係獨立地選自C1 -C6 烷基、羥基、鹵基及經1至3個-OH取代之C1 -C6 烷基； R13 係H或C1 -C6 烷基； R14 係H或C1 -C6 烷基； 各R16 係C1 -C6 烷基； 各R17 獨立地係H或C1 -C6 烷基； 各R18 獨立地係鹵基、-CN、C1 -C6 烷氧基或C1 -C6 烷基； m係1、2、3、4、5或6，及 n係1、2、3、4、5或6。The compound of claim 1 or claim 2, wherein L is -CH 2 - or -CH 2 CH 2 -; Y 1 is -CH 2 - or -CH 2 CH 2 -; Y 2 is -CH 2 - or -CH 2 CH 2 -; Y 3 -CH 2 - or -XCH 2 -; X--CH 2 - or O; R 1 -NHR 6 , -NR 5 R 6 , -NH 2 , -N(R 5 ) 2 , -NHR 5 , -NHR 8 , -N(R 6 R 8 ) or -N(R 6 ) 2 ; R 2 is H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl R 3 is H, C 1 -C 6 alkyl or -CD 3 ; R 4 is H, NH 2 , C 1 -C 6 alkyl or halo; each R 5 is independently C 1 -C 6 alkyl , -CD 3 or -(CH 2 ) n OR 9 ; R 6 is a C 3 -C 6 cycloalkyl group or 4 to 6 having 1 to 2 ring members independently selected from N, NH, NR 16 and O a heterocycloalkyl group which is unsubstituted or substituted with 1 to 2 R 12 groups; each R 8 group is independently selected from C 1 -C 6 haloalkyl, -(C(R 9 ) 2 ) n OR 9 and C 1 -C 6 alkyl substituted by 1 to 3 -OH; each R 12 is independently selected from C 1 -C 6 alkyl, hydroxy, halo and substituted by 1 to 3 -OH C 1 -C 6 alkyl group; R 13 is H or lines C 1 -C 6 alkyl group; R 14 is H or lines C 1 -C 6 alkyl; each R 16 lines C 1 -C 6 alkyl; each R 17 is independently fastened H or C 1 -C 6 alkyl; each R 18 is independently Department of halo, -CN, C 1 -C 6 alkoxy or C 1 -C 6 alkyl; m based 1,2,3,4,5 or 6, and n 1,2,3,4,5-based Or 6. 如請求項1或請求項2之化合物，其中 R6 係具有獨立地選自N、NH及O之1至2個環成員之未經取代之4至6員雜環烷基。The compound of claim 1 or claim 2, wherein R 6 is an unsubstituted 4 to 6 membered heterocycloalkyl group independently selected from 1 to 2 ring members of N, NH and O. 如請求項1或請求項2之化合物，其中 R6 係環丁基、氧雜環丁烷基、哌啶基、吡咯啶基、嗎啉基或氮雜環丁烷基。The compound of claim 1 or claim 2, wherein R 6 is cyclobutyl, oxetanyl, piperidinyl, pyrrolidinyl, morpholinyl or azetidinyl. 如請求項1之化合物，其選自： 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡咯并[2,3-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； 6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷； 4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(2-((4-胺基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-(2-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-2H-吡唑并[4,3-c]吡啶-5(4H)-基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-6-胺； 4-((5-(5-氯-1-甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 1,6-二甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 1,3,5-三甲基-7-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[4,3-d]嘧啶； N-(2-甲氧基乙基)-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 2-(乙胺基)-N-(4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； 4-(4-((3-甲基-5-(6-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 2-(乙胺基)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(氧雜環丁烷-3-基甲基)雙環[2.2.2]辛-1-胺； 3-(二甲基胺基)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)丙醯胺； 4-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-環丁基-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N,N-二環丁基-4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 6-甲基-4-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 6-甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； (3-(((4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)甲基)氧雜環丁烷-3-基)甲醇； N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-甲醯胺； (S)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (S)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； (R)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； 3,6-二甲基-4-(3-甲基-1-((4-嗎啉基雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)異噁唑并[5,4-d]嘧啶； 1,3,5-三甲基-7-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[4,3-d]嘧啶； 1,6-二甲基-4-(3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1H-吡唑并[3,4-d]嘧啶； 4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(三氘甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-(三氟甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-醇； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)甲磺醯胺； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)(甲基)胺甲酸第三丁酯； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸1-甲基環丙酯； 3-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[1.1.1]戊-1-胺； 4-((5-(1-(4-甲氧基苄基)-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-環丁基-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-異丙基雙環[2.2.2]辛-1-胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)丙-1-醇； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-乙基雙環[2.2.2]辛-1-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-7,7-二甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(2,2-二氟乙基)-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； -((3-甲基-5-(2-甲基喹啉-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 1-((4-(氮雜環丁烷-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-7,7-二甲基-4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶-2-基)甲基)雙環[2.2.2]辛-1-胺； 1,1-二氧化4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)硫嗎啉； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(哌啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-醇； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-甲氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-乙氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-雙(2-乙氧基乙基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-N-甲基雙環[2.2.2]辛-1-胺； (3S,4R)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3,4-二醇； (S)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3-醇； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-N,N-二甲基乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-N-甲基氧雜環丁烷-3-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-異丙基-N-甲基雙環[2.2.2]辛-1-胺； N-環丁基-4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-甲基雙環[2.2.2]辛-1-胺； (3S,4S)-1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)吡咯啶-3,4-二醇； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(吡咯啶-1-基)-2-氧雜雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(6-(4-氟苯基)-1-甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-(1-((4-胺基雙環[2.2.2]辛-1-基)甲基)-3-甲基-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)吡啶-2-基)苄腈； 3-甲基-5-(2-苯基吡啶-4-基)-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 2-甲基-4-(3-甲基-1-((4-(吡咯啶-1-基)雙環[2.2.2]辛-1-基)甲基)-6,7-二氫-1H-吡唑并[4,3-c]吡啶-5(4H)-基)-1,7-萘啶； 4-((5-(2-(4-氟苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(2-(2-氟-4-甲基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-(2-(4-甲氧基苯基)吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-(對甲苯基)吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(2-(5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)乙基)雙環[2.2.2]辛-1-胺； 4-((5-(2,8-二甲基-1,7-萘啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((3-甲基-5-(2-甲基-6-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-((5-([2,2'-聯吡啶]-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-1-((4-(哌啶-1-基)-2-氧雜雙環[2.2.2]辛-1-基)甲基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(1-甲氧基丙-2-基)雙環[2.2.2]辛-1-胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-乙基-N-甲基雙環[2.2.2]辛-1-胺； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N,N-二甲基-2-氧雜雙環[2.2.2]辛-4-胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-1-(哌啶-1-基)乙酮； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(吡咯啶-1-基)乙醯胺； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基-2-甲基丙基)雙環[2.2.2]辛-1-胺； 1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-N-(2-甲氧基乙基)-2-氧雜雙環[2.2.2]辛-4-胺； 4-((5-(2-氯-5,7-二氫呋喃并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； 4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-1-甲基哌嗪-2-酮； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(二甲基胺基)丙醯胺； 2-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-1-(吡咯啶-1-基)乙酮； (R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲基嗎啉； 1-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基哌嗪-2-酮； (S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-甲基嗎啉； (2S,6R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； (2S,6S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； N-(環丁基甲基)-1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； (2R,6R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2,6-二甲基嗎啉； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(乙胺基)乙醯胺； 3-胺基-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)丙醯胺； 6-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)丙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)丙醯胺； 1-((4-(1H-咪唑-1-基)雙環[2.2.2]辛-1-基)甲基)-5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶； (1R,5S)-3-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-8-氧雜-3-氮雜雙環[3.2.1]辛烷； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(甲胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-4-甲基嗎啉-3-甲醯胺； 1-((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)-2-甲基丙-2-醇； 2-(乙胺基)-N-(4-((3-甲基-5-(5-甲基-1H-吡唑并[4,3-b]吡啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-2-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(乙胺基)丙醯胺； N-乙基-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (S)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-甲基嗎啉； (R)-4-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-甲基嗎啉； N-(2-甲氧基乙基)-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氮雜環丁烷-3-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(乙基(甲基)胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-氟氮雜環丁烷-1-基)乙醯胺； 2-(雙(三氘甲基)胺基)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-羥基乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(3-羥基氮雜環丁烷-1-基)乙醯胺； (3-(((4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺基)甲基)氧雜環丁烷-3-基)甲醇； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(N-甲基甲基磺醯胺基)乙醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(N-甲基乙醯胺基)乙醯胺； 4-((3-甲基-5-(6-甲基-1-(三氘甲基)-1H-吡唑并[3,4-b]吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (S)-N-(4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-3-(甲胺基)丙醯胺； N-環丁基-1-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)-2-氧雜雙環[2.2.2]辛-4-胺； N-環丁基-4-((3-甲基-5-(2-苯基吡啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺； (4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((3-甲基-5-(2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((3-甲基-5-(2-甲基-1,7-萘啶-4-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)胺甲酸第三丁酯； (4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.1]庚-1-基)胺甲酸第三丁酯； 4-((5-(1,6-二甲基-1H-吡唑并[3,4-d]嘧啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺，及 4-((5-(1-乙基-6-甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-胺。A compound according to claim 1, which is selected from the group consisting of: 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((3- Methyl-5-(6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-( (3-Methyl-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrrolo[2,3- b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] oct-1-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)oxetane- 3-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(dimethylamino)acetamide; (S)-N-(4-((5-(1, 6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; (R)-N-(4-((5-(1,6) -Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; 6-(4-((3-methyl-5-(1,3) ,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-oxa-6-azaspiro[3.3]heptane; 4-(1-((4-aminobicyclo)[ 2.2.2] Oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl-1H- Pyrazolo[3,4-d]pyrimidin-6-amine; 4-(2-((4-aminobicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro- 2H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine; 4-(1- ((4-Aminobicyclo[2.2.2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 ( 4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-amine; 4-(2-((4-aminobicyclo[2.2.2]oct-1-yl)methyl)-3-methyl-6,7-dihydro-2H-pyrazolo[ 4,3-c]pyridine-5(4H)-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine; 4-((5-(5-chloro-) 1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 1,6-dimethyl-4-(3-methyl-1-((4-(pyrrolidin-1) -yl)bicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H- Pyrazolo[3,4-d]pyrimidine; 1,3,5-trimethyl-7-(3-methyl-1-((4-(pyrrolidin-1-yl))bicyclo[2.2.2] Oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[4,3-d Pyrimidine; N-(2-methoxyethyl)-4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine) -7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine; 2-(ethylamino)-N-( 4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]] Pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl Ethylamine; 4-(4-((3-methyl-5-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5,6, 7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine; 2-(ethylamino)-N -(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7 -tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)acetamide; 4-((3-methyl-) 5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-1-yl)methyl)-N-(oxetan-3-ylmethyl)bicyclo[2.2.2]oct-1-amine; 3-(dimethylamino) )-N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)propanamine; 4-(4-( (3-Methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine; 4-((3-methyl-5-(1,3) ,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; N-cyclobutyl-4 -((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; N,N-dicyclobutyl-4-((3-) 5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 6-methyl-4-(3-methyl-1-((4-(piperidine)) -1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)- 1H-pyrazolo[3,4-d]pyrimidine; 6-methyl-4-(3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oct-1 -yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[3,4-d]pyrimidine; (3-((4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)methyl)oxyheterocycle Butane-3-yl)methanol; N-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine-7-) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridyl -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)azetidin-3-carboxamide; (S)-N-(4-((3-methyl-5-) (1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; (S)-N-(4-((3-methyl-5) -(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-2-carboxamide; (R)-N-(4-((3-methyl-) 5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; (R)-N-(4-((3-methyl) -5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-2-carboxamide; 3,6-dimethyl-4-(3-methyl -1((4-morpholinylbicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 ( 4H)-yl)isoxazo[5,4-d]pyrimidine; 1,3,5-trimethyl-7-(3-methyl-1-((4-(piperidin-1-yl)) Bicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazole And [4,3-c]pyridine-5(4H)-yl)-1H-pyrazolo[4,3-d]pyrimidine; 1,6-dimethyl-4-(3-methyl-1- ((4-(piperidin-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5 (4H)-yl)-1H-pyrazolo[3,4-d]pyrimidine; 4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4] ,3-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-double (trimethylene)bicyclo[2.2.2]oct-1-amine; 4-((3-methyl-5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((3-A 5-(1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2 -yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl )-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-dimethylbicyclo[2.2 .2] oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]heptan-1-amine; 4-((5-(1) ,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-(trifluoro -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-( (5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyridyl Zoxao[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-ol; N-(4-((5-(1,6-dimethyl-1H-) Pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl )methyl)bicyclo[2.2.2]oct-1-yl)acetamidamine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] Octan-1-yl)methanesulfonamide; (4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)(methyl)amine Tert-butyl formate; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6 ,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]oct-1-amine; (4-((5) -(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] oct-1-yl) carbamic acid 1-methylcyclopropyl ester; 3-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) )-3-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-2-yl)methyl)bicyclo[1.1.1]pentan-1-amine 4-((5-(1-(4-methoxybenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; N-cyclobutyl-4 -((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-py) Zoxao[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Methyl)-N-isopropylbicyclo[2.2.2]oct-1-amine; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4- b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2. 2] oct-1-yl)amino)propan-1-ol; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-ethylbicyclo[2.2.2] octyl 1-amine; 5-(1,6-dimethyl-1H-pyrazole [3,4-b]pyridin-4-yl)-3-methyl-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4 ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3, 4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2] oct-1-yl)morpholine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7 - dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; N -(2,2-difluoroethyl)-4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; -((3- Methyl-5-(2-methylquinolin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Bicyclo[2.2.2]oct-1-amine; 4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 1-((4-(azetidin-1-yl)bicyclo[2.2. 2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(1, 6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-7,7-dimethyl-4,5,6,7-tetrahydro-2H-pyrazolo[ 4,3-c]pyridin-2-yl)methyl)bicyclo[2.2.2]oct-1-amine; 1,1-di-2-(4-((5-(1,6-dimethyl)) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 1-yl)methyl)bicyclo[2.2.2]oct-1-yl)thiomorpholine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-1-((4-(piperidin-1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridine; 1-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)nitrogen Heterocyclic butan-3-ol; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxyethyl)bicyclo[2.2.2]octine- 1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7 -tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-bis(2-methoxyethyl)bicyclo[2.2.2]oct-1- Amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)- N-(2-ethoxyethyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N,N-double (2-ethoxyethyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-N-(2-methoxy (ethyl 5-)-N-methylbicyclo[2.2.2]oct-1-amine; (3S,4R)-1-(4-((5-(1,6-dimethyl-1H-pyrazole) [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl Bis[2.2.2]oct-1-yl)pyrrolidine-3,4-diol; (S)-1-(4-((5-(1,6-dimethyl-1H-pyrazole) [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl Bicyclo[2.2.2]oct-1-yl)pyrrolidin-3-ol; 2-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b] Pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2 ] oct-1-yl)amino)-N,N-dimethylacetamide; N-(4-(( 5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-N-methyloxetan-3-amine; 4-((5- (1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-1-yl)methyl)-N-isopropyl-N-methylbicyclo[2.2.2]oct-1-amine; N-cyclobutyl-4-((5- (1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-1-yl)methyl)-N-methylbicyclo[2.2.2]oct-1-amine; (3S,4S)-1-(4-((5-(1, 6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3 -c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)pyrrolidine-3,4-diol; 1-((5-(1,6-dimethyl-1H) -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1- Methyl)-2-oxabicyclo[2.2.2]oct-4-amine; 5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl --3-methyl-1-((4-(pyrrolidin-1-yl)-2-oxabicyclo[2.2.2]oct-1-yl)methyl)-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(6-) (4-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-(4-(1-4-aminobicyclo[2.2.2 Octyl-1-yl)methyl)-3-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)pyridin-2-yl) Benzonitrile; 3-methyl-5-(2-phenylpyridin-4-yl)-1-((4-(pyrrolidin-1-yl)bicyclo[2.2.2]oct-1-yl)methyl -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 2-methyl-4-(3-methyl-1-((4-(pyrrolidine)- 1-yl)bicyclo[2.2.2]oct-1-yl)methyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-yl)-1 , 7-naphthyridine; 4-((5-(2-(4-fluorophenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((5-(2-(2-fluoro-4-methylphenyl)pyridine) 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2] octyl 1-amine; 4-((5-(2-(4-methoxyphenyl)pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((3-methyl-5-(2-(p-tolyl))pyridine- 4-yl)-4,5,6,7-tetrahydro-1H-pyridyl And [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-(2-(5-(1,6-dimethyl-1H-pyrazole) And [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Bis)bicyclo[2.2.2]oct-1-amine; 4-((5-(2,8-dimethyl-1,7-naphthyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-((3-methyl-5) -(2-methyl-6-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl) Bicyclo[2.2.2]oct-1-amine; 4-((5-([2,2'-bipyridyl)-4-yl)-3-methyl-4,5,6,7-tetrahydro- 1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 5-(1,6-dimethyl-1H-pyrazolo[ 3,4-b]pyridin-4-yl)-3-methyl-1-((4-(piperidin-1-yl)-2-oxabicyclo[2.2.2]oct-1-yl) A -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3] ,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)- N-(1-methoxypropan-2-yl)bicyclo[2.2.2]oct-1-amine; 4-((5-(1,6-dimethyl-1H-pyrazolo[3,4] -b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[ 4,3-c]pyridin-1-yl)methyl)-N-ethyl-N-methylbicyclo[2.2.2]oct-1-amine; 1-((5-(1,6-dimethyl) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)-N,N-dimethyl-2-oxabicyclo[2.2.2]oct-4-amine; 2-((4-((5-(1,6-dimethyl)) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)-1-(piperidin-1-yl)ethanone; N-(4-((5-(1,6) -Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(pyrrolidin-1-yl)acetamide; 4-((5-(1,6-di) Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] Pyridin-1-yl)methyl)-N-(2-methoxy-2-methylpropyl)bicyclo[2.2.2]oct-1-amine; 1-((5-(1,6-di) Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] Pyridin-1-yl)methyl)-N-(2-methoxyethyl)-2-oxabicyclo[2.2.2]oct-4-amine; 4-((5-(2-chloro-5) ,7-dihydrofuro[3,4-d]pyrimidin-4-yl)-3-methyl- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; 4-(4-( (5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyridyl Zoxa[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-1-methylpiperazin-2-one; N-(4-((5) -(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-3-(dimethylamino)propanamine; 2-((4-(( 5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole And [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)-1-(pyrrolidin-1-yl)ethanone; (R)- 4-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-methylmorpholine; 1-(4-( (5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyridyl (Z)-[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-4-methylpiperazin-2-one; (S)-4-(4 -((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)- 2-methylmorpholine; (2S,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-) 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)- 2,6-dimethylmorpholine; (2S,6S)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- -2,6-dimethylmorpholine; N-(cyclobutylmethyl)-1-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine- 4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2-oxabicyclo[2.2 .2] oct-4-amine; (2R,6R)-4-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl) --3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl -2,6-dimethylmorpholine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3) -methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2 -(ethylamino)acetamide; 3-amino-N-(4-((5-(1,6-II) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine -1-yl)methyl)bicyclo[2.2.2]oct-1-yl)propanamine; 6-(4-((5-(1,6-dimethyl-1H-pyrazolo[3, 4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2] Oct-1-yl)-2-oxa-6-azaspiro[3.3]heptane; (R)-N-(4-((5-(1,6-dimethyl-1H) -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1- ()-(N-(4-(1,6-dimethyl)) -1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine- 1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(methylamino)propanamine; 1-((4-(1H-imidazol-1-yl)bicyclo[2.2. 2]oct-1-yl)methyl)-5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; (1R,5S)-3-(4-((5-(1,6-dimethyl-1H-pyrazole) And [3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl) Bis)bicyclo[2.2.2]oct-1-yl)-8-oxa-3-azabicyclo[3.2 .1]octane; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(methylamino) Acetamine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-4-methylmorpholine-3- Formamide; 1-((4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5 ,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)-2-methylpropane 2-ol; 2-(ethylamino)-N-(4-((3-methyl-5-(5-methyl-1H-pyrazolo[4,3-b]pyridin-7-yl) -4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)acetamide; N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-2-carboxamide; N-(4- ((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- --3-(ethylamino)propanamide; N-ethyl-4-((3-methyl-5-(2-phenylpyridin-4-yl)-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; (S)-4-(4-((5-(1) ,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4, 3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-3-methylmorpholine; (R)-4-(4-((5-(1,6) -Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-3-methylmorpholine; N-(2-methoxyethyl)-4-((3-A) 5-(2-phenylpyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[ 2.2.2] Oct-1-amine; N-(4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) 4-,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)azetidine Alkyl-3-carboxamide; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-) 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(ethyl (methyl)amino)acetamide; N-(4-((5-(1,6-) Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] Pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(3-fluoroazetidin-1-yl)acetamide; 2-(double (trim) -amino)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4, 5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)acetamide; N-(4 -((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H -pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-hydroxyacetamidine; N-(4-((5-( 1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(3-hydroxyazetidin-1-yl)acetamide; (((4-((5-(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7- Tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)amino)methyl)oxetane-3- Methanol); N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5, 6,7-tetrahydro-1H-pyrazolo[4,3- c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(N-methylmethylsulfonylamino)acetamide; N-(4-((5) -(1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazole [4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(N-methylacetamido)acetamide; 4-((3 -methyl-5-(6-methyl-1-(trimethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)-4,5,6,7-tetrahydro -1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; (S)-N-(4-((5-(1- Ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4 ,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3-carboxamide; N-(4-((5-(1,6-II) Methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] Pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-3-(methylamino)propanamine; N-cyclobutyl-1-((5-(1,6-) Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c Pyridin-1-yl)methyl)-2-oxabicyclo[2.2.2]oct-4-amine; N-cyclobutyl-4-((3-methyl-5-(2-phenylpyridine) -4-yl)-4,5,6,7-tetrahydro-1H- Pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-amine; (4-((5-(1-ethyl-6-methyl-1H) -pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1- (3)-(2-methyl-5-(2-methyl-7H-pyrrolo[2,3] -d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]xin- 1-butyryl carboxylic acid tert-butyl ester; (4-((3-methyl-5-(2-methyl-1,7-naphthyridin-4-yl)-4,5,6,7-tetra Hydrogen-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)aminecarboxylic acid tert-butyl ester; (4-((5-( 1,6-Dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4 , 3-c]pyridin-1-yl)methyl)bicyclo[2.2.1]hept-1-yl)aminecarboxylic acid tert-butyl ester; 4-((5-(1,6-dimethyl-1H-) Pyrazolo[3,4-d]pyrimidin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl )methyl)bicyclo[2.2.2]oct-1-amine, and 4-((5-(1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-4- 3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1- amine. 如請求項1之化合物，其選自： N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)氧雜環丁烷-3-胺； N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-(二甲基胺基)乙醯胺； (S)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺； (R)-N-(4-((5-(1,6-二甲基-1H-吡唑并[3,4-b]吡啶-4-基)-3-甲基-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)嗎啉-3-甲醯胺，及 6-(4-((3-甲基-5-(1,3,5-三甲基-1H-吡唑并[4,3-d]嘧啶-7-基)-4,5,6,7-四氫-1H-吡唑并[4,3-c]吡啶-1-基)甲基)雙環[2.2.2]辛-1-基)-2-氧雜-6-氮雜螺[3.3]庚烷。A compound according to claim 1, which is selected from the group consisting of: N-(4-((5,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3- Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)oxirane Butane-3-amine; N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4) ,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-(dimethyl Amino)acetamide; (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) Methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine- 3-methylamine; (R)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-) 4-,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)morpholine-3 -Procarbamide, and 6-(4-((3-methyl-5-(1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl))- 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]oct-1-yl)-2-oxa- 6-azaspiro[3.3]heptane. 一種醫藥組合物，其包含治療有效量之如請求項1至13中任一項之化合物及醫藥上可接受之載劑。A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier. 一種如請求項1至13中任一項之化合物在製造用於治療與選自TLR7、TLR8及TLR9或其組合之胞內體類鐸(Toll-like)受體之活性相關聯之自體免疫疾病之藥劑中之用途。A compound according to any one of claims 1 to 13 for use in the manufacture of an autoimmune antibody for the treatment of an activity associated with an endosome toll-like receptor selected from the group consisting of TLR7, TLR8 and TLR9 or a combination thereof Use in the agent of the disease. 一種如請求項1至13中任一項之化合物在製造用於治療與選自TLR7通路、TLR8通路及TLR9通路或其組合之胞內體類鐸受體通路之活性相關聯之自體免疫疾病之藥劑中之用途。A compound according to any one of claims 1 to 13 for use in the manufacture of an autoimmune disease associated with the activity of an endosome receptor receptor pathway selected from the group consisting of the TLR7 pathway, the TLR8 pathway and the TLR9 pathway, or a combination thereof The use of the medicament. 一種如請求項1至13中任一項之化合物在製造用於治療與以下相關聯之自體免疫疾病之藥劑中之用途， i) TLR7活性，或 ii) TLR7活性及TLR8活性，或 iii) TLR7活性及TLR8活性及TLR9活性。A use of a compound according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of an autoimmune disease associated with i) TLR7 activity, or ii) TLR7 activity and TLR8 activity, or iii) TLR7 activity and TLR8 activity and TLR9 activity. 如請求項15至17中任一項之用途，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。The use according to any one of claims 15 to 17, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenia Purpura, suppurative sweat glands, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. 一種如請求項1、2、12及13中任一項之化合物，其用於治療自體免疫疾病。A compound according to any one of claims 1, 2, 12 and 13, for use in the treatment of an autoimmune disease. 如請求項19之化合物，其中該自體免疫疾病係全身性紅斑狼瘡、皮膚狼瘡、盤狀狼瘡、混合型結締組織疾病、原發性膽汁性肝硬化、免疫性血小板減少性紫癜、化膿性汗腺炎、皮肌炎、多肌炎、休格倫症候群、關節炎、類風濕性關節炎或牛皮癬。The compound of claim 19, wherein the autoimmune disease is systemic lupus erythematosus, cutaneous lupus, discoid lupus, mixed connective tissue disease, primary biliary cirrhosis, immune thrombocytopenic purpura, suppurative sweat gland Inflammation, dermatomyositis, polymyositis, Hugh's syndrome, arthritis, rheumatoid arthritis or psoriasis. 一種組合，其包含治療有效量之如請求項1至13中任一項之化合物及一或多種額外之治療劑，其中該額外之治療劑係獨立地選自抗炎劑、免疫調節劑、免疫抑制劑、細胞介素、非類固醇抗炎藥物(NSAID)、抗瘧化合物、抗風濕化合物、B細胞活化因子(BAFF)之抑制劑、B淋巴細胞刺激劑(BLyS)之抑制劑及類固醇激素。A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 13 and one or more additional therapeutic agents, wherein the additional therapeutic agent is independently selected from the group consisting of an anti-inflammatory agent, an immunomodulator, and an immunization Inhibitors, interleukins, non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial compounds, antirheumatic compounds, inhibitors of B cell activating factor (BAFF), inhibitors of B lymphocyte stimulator (BLyS), and steroid hormones.
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