CN116745278A

CN116745278A - Enzyme inhibitors

Info

Publication number: CN116745278A
Application number: CN202180092541.XA
Authority: CN
Inventors: 米切尔·刘易斯·蔡尔兹; 丽贝卡·路易丝·戴维; 汉娜·乔伊·爱德华兹; 戴维·米歇尔·埃万斯; 威廉·杰克·格雷夫斯; 西蒙·泰亚比·霍奇森; 亚历山德罗·马扎卡尼; 卡尔·莱斯利·诺斯; 阿莉恰·斯特拉·奥巴拉; 迈克尔·布莱恩·罗伊; 戴维·菲利普·鲁克; 迈克尔·约翰·斯托克斯; 路易斯·米歇尔·伯奇; 马克·皮乔维茨; 蕾切尔·皮塔韦; 阿伦·约翰·史密斯; 亚当·埃里克·斯鲁普; 约瑟夫·威廉·里格尔斯沃思; 杨学峥; 戴维·爱德华·克拉克
Original assignee: Kalvista Pharmaceuticals Ltd
Current assignee: Kalvista Pharmaceuticals Ltd
Priority date: 2020-12-01
Filing date: 2021-12-01
Publication date: 2023-09-12

Abstract

The present invention provides compounds of formula (I): compositions comprising such compounds; the application of the compounds in medicines; and methods of treating patients with such compounds; wherein A, W, R, n, Z, X, Y and B are as defined herein. The invention also relates to compounds useful as synthesis intermediates for the compounds of formula (I).

Description

Enzyme inhibitors

Technical Field

The present invention relates to enzyme inhibitors as inhibitors of factor XIIa (FXIIIa) and to pharmaceutical compositions comprising such inhibitors and to the use of such inhibitors.

Background

The compounds of the invention are inhibitors of factor XIIa (FXIIa) and thus have a variety of possible therapeutic applications, particularly for the treatment of diseases or conditions associated with factor XIIa inhibition.

FXIIa is a serine protease (EC 3.4.21.38) derived from its zymogen precursor expressed by the F12 gene: factor XII (FXII). Single-chain FXII has a low level of amidolytic activity, which increases upon interaction with a negatively charged surface and has been associated with its activation (see Invanov et al, blood.2017, month 3, 16; 129 (11): 1527-1537. Digital object identifier: 10.1182/blood-2016-10-744110). Proteolytic cleavage of FXII into FXIIa heavy and light chains leads to a significant enhancement of catalytic activity. FXIIa that retains its complete heavy chain is αfxiia. The small fragment of FXIIa that retains its heavy chain is beta FXIIa. The individual catalytic activities of αfxiia and βfxiia contribute to FXIIa activation and biochemical function. Mutations and polytypes of the F12 gene can alter FXII and FXIIIa cleavage.

FXIIa has a unique specific structure that differs from many other serine proteases. For example, tyr99 in FXIIa points to the active site, thereby partially blocking the S2 pocket and conferring its blocking characteristics. Other serine proteases containing Tyr99 residues (e.g., FXa, tPA and FIXa) have a more open S2 pocket. Furthermore, among several trypsin-like serine proteases, the P4 pocket is lined with an "aromatic box" responsible for P4 driving activity and selectivity of the corresponding inhibitor. However, FXIIa has an incomplete "aromatic box" resulting in a more open P4 pouch. See, e.g., "Crystal structures of the recombinant beta-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics" M.Pathak et al, acta.Cryst.2019, D75,1-14; "Structures of human plasma beta-factor XIIa cocrystallized with potent inhibitors" A Dementiev et al, blood Advances 2018,2 (5), 549-558; "Design of Small-molecular Active-Site Inhibitors of the S1A Family Proteases as Procoagulant and Anticoagulant Drugs" P.M.Fischer, J.Med.Chem.,2018,61 (9), 3799-3822; "Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation" B.K.Hamad et al Journal of Thrombosis and Haemostasis,15:1818-1828.

FXIa converts Prekallikrein (PK) to plasma kallikrein (PKa), thereby allowing positive feedback activation of FXII to FXIa. FXII, PK and high molecular weight kininogen (HK) collectively represent the contact system. FXIIa mediated conversion of plasma prekallikrein to plasma kallikrein can cause subsequent cleavage of HK to produce bradykinin, a potent inflammatory hormone that can also increase vascular permeability, which is associated with conditions such as Hereditary Angioedema (HAE). The contact system is activated via a variety of mechanisms including interactions with negatively charged surfaces, negatively charged molecules, unfolded proteins, artificial surfaces, foreign tissues (e.g., biological grafts, including biological heart valves, and organ/tissue grafts), bacteria, and biological surfaces (including endothelial cells and extracellular matrix), which mediate the assembly of the components of the contact system. In addition, the contact system is activated by plasmin and FXII cleavage by other enzymes can promote its activation.

Activation of the contact system causes activation of the kallikrein-kallikrein system (KKS), complement system and endogenous coagulation pathway (see https:// www.genome.jp/kegg-bin/show_path wap 04610). In addition, other substrates of FXIIa can contribute directly and indirectly to the biological activity of FXI Ia via PKa, including protease-activated receptor (PAR), plasminogen, and neuropeptide Y (NPY). Inhibition of FXIIa can provide clinical benefit by treating diseases and conditions associated with these systems, pathways, receptors and hormones.

PKa activation of PAR2 mediates neuroinflammation and can cause neuroinflammatory disorders including multiple sclerosis (seeEt al, proc Natl Acad Sci U S a.2019, 1, 2; 116 271-276. Digital object identifier: 10.1073/pnas.1810020116). PKa activation of PAR1 and PAR2 on vascular smooth muscle cells is associated with vascular hypertrophy and atherosclerosis (see Abdallah et al, J Biol chem.2010, 5 th, 285 (45): 35206-15. Digital object identifier: 10.1074/jbc. M110.171769). Activation of FXIa by plasminogen to plasmin results in fibrinolysis (see Koning et al, thromb Res.2015, 8; 136 (2): 474-80. Digital object identifier: 10.1016/j. Thromres.2015.06.028). PKa proteolytically cleaves NPY and thereby alters its binding to the NPY receptor (Abid et al, J Biol chem.2009, 9/11; 284 (37): 24715-24. Digital object identifier: 10.1074/jbc.M 109.035253). Inhibition of FXIIa can provide clinical benefit by treating diseases and conditions caused by PAR signaling, NPY metabolism, and plasminogen activation.

FXIa mediated activation of KKS results in the production of Bradykinin (BK) which may mediate, for example, vascular edema, pain, inflammation, vascular hyperpermeability and vasodilation (see Kaplan et al, adv immunol.2014;121:41-89. Digital object identifier: 10.1016/B978-0-12-800100-4.00002-7; and Hopp et al, J neuroin animation.2017, month 2, 20; 14 (1): 39. Digital object identifier: 10.1186/s 12974-017-0815-8). A phase 2 study of the monoclonal antibody, gaboxamab (CSL-312) inhibiting FXIa, has recently been completed, wherein monthly prophylactic subcutaneous treatment has been reported to be well tolerated and effective in preventing the onset of type I/type II Hereditary Angioedema (HAE) in patients with type I/type II hereditary angioedema disease Causing intermittent face, hand, throat, gastrointestinal and genital swelling (see https:// www.clinicaltrials.gov/ct2/show/NCT03712228 and Crai g et al 1451, allergy.2020;75 (journal 109): 5-99. Digital object identifier: 10.1111/all.14504). The etiology of mutations in FXII that promote its activation to FXIIa to HAE has been identified (seeEt al, J Clin invest.2015 8, 3; 125 3132-46. Digital object identifier: 10.1172/JCI77139; and de Maat et al, J allegy Clin immunol.2016, 11; 138 1414-1423.e9. Digital object identifier: 10.1016/j.jaci.2016.02.021). Since FXIIa mediates PK production, FXIIa inhibitors can provide protection against all forms of BK-mediated angioedema, including HA E and non-hereditary bradykinin-mediated angioedema (BK-AEnH).

"hereditary angioedema" can be defined as any condition characterized by recurrent episodes of bradykinin-mediated angioedema (e.g. severe swelling) caused by inherited genetic dysfunctions/defects/mutations. There are currently three known categories of HAEs: (i) HAE type 1, (ii) HAE type 2 and (iii) normal C1 inhibitor HAE (normal C1-Inh HAE). However, work on characterizing HAE etiology is underway, so it is expected that other types of HAEs may be defined in the future.

Without wishing to be bound by theory, it is believed that HAE type 1 is caused by a mutation in the SERPING1 gene that causes a decrease in the level of C1 inhibitor in the blood. Without wishing to be bound by theory, it is believed that HAE type 2 is caused by a mutation in the SERPING1 gene that causes the C1 inhibitor in the blood to function abnormally. Without wishing to be bound by theory, the definition of the cause of normal C1-Inh HAE is less well defined and the underlying gene dysfunction/defect/mutation may sometimes remain unknown. The etiology of normal C1-Inh HAE is known to be independent of reduced levels of C1 inhibitor or dysfunctions (compared to type 1 and type 2 HAE). Normal C1-Inh HAE can be diagnosed by checking family history and finding that angioedema is inherited from the previous generation (and therefore, it is hereditary angioedema). Normal C1-Inh HAE can also be diagnosed by determining the presence of functional abnormalities/defects/mutations in the gene other than those associated with the C1 inhibitor. For example, it has been reported that dysfunctions/defects/mutations in plasminogen can cause normal C1-Inh HAE (see, e.g., veronez et al, front Med (Lausanne). 21.2019; 6:28. Digital object identifier: 10.3389/fmed.2019.00028; or Reck et al, clin Transl allergy.2019, 14.2. 9:9. Digital object identifier: 10.1186/s 13601-019-0247-x.). It has also been reported that dysfunctions/defects/mutations of factor XII may cause normal C1-Inh HAE (see e.g.Mansi et al 2014The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine,2015,277;585-593; or Maat et al J Thromb Haemost.2019, month 1; 17 (1): 183-194. Digital object identifier: 10.1111/jth.14325).

However, angioedema is not necessarily inherited. Indeed, another type of angioedema is bradykinin-mediated non-hereditary angioedema (BK-AEnH) which is not caused by genetic gene dysfunction/deficiency/mutation. The underlying cause of BK-AEnH is generally unknown and/or undefined. However, the signs and symptoms of BK-AEnH are similar to those of HAE, not being bound by theory, it is believed that this is due to the shared bradykinin-mediated pathway between HAE and BK-AEnH. In particular, BK-AEnH is characterized by recurrent episodes in which body fluids accumulate outside blood vessels, blocking the normal flow of blood or lymph and causing rapid swelling of tissues such as hands, feet, limbs, face, intestinal tract, respiratory tract or genitals.

Specific types of BK-AEnH include: non-hereditary angioedema (AE-nC 1 Inh) in the presence of normal C1 inhibitors, which may be environmental, hormonal or drug induced; acquired angioedema; vascular edema associated with allergy; angioedema induced by Angiotensin Converting Enzyme (ACE) inhibitors; dipeptidyl peptidase 4 inhibitor induced angioedema; and tPA-induced angioedema (tissue plasminogen activator-induced angioedema). However, it is not known why these factors and conditions cause angioedema in only a relatively small proportion of individuals.

Environmental factors that can induce AE-nC1 include air pollution (Kedarisetty et al Otolaryngol Head Neck Surg.2019, 30 th. 194599819846446. Digital object identifier: 10.1177/0194599819846446) and silver nanoparticles such as those used as antimicrobial components in medical, biomedical and consumer products (Long et al nanotechnology. 2016;10 (4): 501-11. Digital object identifier: 10.3109/17435390.2015.1088589).

Various publications propose the association between bradykinin and contact system pathways and BK-AEnH as well as the potential efficacy of treatment, see for example: bas et al (N Engl J Med 2015; leibfred and Kovari. J Pharm practice 2017); van den Elzen et al (Clinic Rev Allerg Immunol 2018); han et al (JCI 2002).

AE treated with BK, for example, may be due to thrombolytic therapy. tPA-induced angioedema is discussed in various publications as a potentially life-threatening complication following thrombolytic therapy in acute stroke victims (see, e.g.Blood.2017, 4, 20; 129 2280-2290. Digital object identifier: 10.1182/blood-2016-09-740670; />Serial.2019, 6, 11, STROKEAHA119025260. Digital object identifier: 10.1161/STROKEAHA.119.025260; rathbun, oxf Med Case reports.2019, 1 month 24 days; 2019 Omy112. Digital object identifier: 10.1093/omcr/omy112; lekoubou et al, neurol res.2014, month 7; 36 687-94. Digital object identifier: 10.1179/1743132813y.0000000302; hill et al, neurology.2003, 5, 13; 60 (9):1525-7).

Stone et al (Immunol Allergy Clin North am.2017, month 8; 37 (3): 483-495.) reported that certain drugs may cause vascular edema.

Scott et al (Curr Diabetes Rev.2018;14 (4): 327-333. Digital object identifier: 10.2174/1573399813666170214113856) reported cases of dipeptidyl peptidase-4 inhibitor induced vascular edema.

Hermannrud et al (BMJ Case Rep.2017, 1/10; 2017.Pii: bcr 201617802) report recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV and also discuss acquired angioedema associated with angiotensin converting enzyme inhibitors (ACEI-AAE). Kim et al (Basic Clin Pharmacol Toxicol.2019, month 1; 124 (1): 115-122. Digital object identifier: 10.1111/bcpt.13097) reported angiotensin II receptor blocker (ARB) related vascular edema. Reichman et al (Pharmacoepidemiol Drug Saf.2017, month 10; 26 (10): 1190-1196. Digital object identifier: 10.1002/pds.4260) also reported the risk of vascular edema in patients using ACE inhibitors, ARB inhibitors, and beta blockers. Diestro et al (J Stroke Cerebrovasc Dis.2019, month 5; 28 (5): e44-e45. Digital object identifier: 10.1016/j. Jstrokeerbroofasdis.2019.01.030) also reported a possible association between certain vascular oedema and ARB.

Giard et al (Dermatology.2012; 225 (1): 62-9. Digital object identifier: 10.1159/000340029) report that bradykinin-mediated vascular edema may be termed "estrogen-related vascular edema" due to estrogen contraceptive precipitation.

Contact system mediated KKS activation has also been associated with retinal edema and diabetic retinopathy (see Liu et al, biol chem.2013, month 3; 394 (3): 319-28. Digital object identifier: 10.1515/hsz-2012-0316). The concentration of FXIia in the vitreous humor of patients with advanced diabetic retinopathy and Diabetic Macular Edema (DME) is increased (see Gao et al, nat Med.2007, 2. Month; 13 (2): 181-8.Epub, 1. Month 28, and Gao et al, J Proteome Res.2008, 6. Month; 7 (6): 2516-25. Digital object identifier: 10.1021/pr800112 g). FXIa is associated with mediating both Vascular Endothelial Growth Factor (VEGF) -independent DME (see Kita et al, diabetes.2015, month 10; 64 (10): 3588-99. Digital object identifier: 10.2337/db 15-0317) and VEGF-mediated DME (see Clermont et al, invest Ophthalmol Vis Sci.2016, month 5, day 1; 57 (6): 2390-9. Digital object identifier: 10.1167/iovs.15-18272). FXII deficiency prevents VEGF-induced retinal edema in mice (Clermont et al, ARVO talk 2019). Thus, FXIIa inhibition has been proposed to provide therapeutic effects against diabetic retinopathy and retinal edema due to retinal vascular hyperpermeability, including DME, retinal vein occlusion, age-related macular degeneration (AMD).

As mentioned above, the contact system can be activated by interaction with bacteria and, thus, FXIIa is involved in the treatment of sepsis and bacterial sepsis (see Morrison et al,J Exp Med.9 months 1 in 1974; 140 (3):797-811). Thus, FXIIa inhibitors may provide therapeutic benefit in the treatment of sepsis, bacterial sepsis, and Disseminated Intravascular Coagulation (DIC).

FXIa mediated KKS activation and BK production has been implicated in neurodegenerative diseases including Alzheimer's disease, multiple sclerosis, epilepsy and migraine (see Zamoldchikov et al, proc Natl Acad Sci U S A.2015, 31. 3/31; 112 (13): 4068-73. Digital object identifier: 10.1073/pnas.1423764112;et al, J Neurochem.2019, 8; 150 296-311. Digital object identifier: 10.1111/jnc.14793; />Et al, nat Commun.2016, 5, 18; 7:11626. Digital object identifier: 10.1038/ncomms11626; and https:// clinicaltrias.gov/ct 2/show/NCT 03108469). Thus, FXIIa inhibitors may provide therapeutic benefit in reducing the progression and clinical symptoms of these neurodegenerative diseases.

FXIIIa is also associated with Allergy (see, bender et al, front immunol.2017, 9, 15; 8:1115. Digital object identifier: 10.3389/fimmu.2017.01115; and Sala-Cunill et al, J Allergy Clin immunol.2015, 4; 135 (4): 1031-43.e6. Digital object identifier: 10.1016/j.jaci.2014.07.057). Thus, FXIIa inhibitors may provide therapeutic benefit in reducing the clinical severity and incidence of allergic reactions.

Biochemical, pharmacological, genetic and molecular studies have been used to identify FXIIa as clotting 50 years agoThe effects in blood and have been widely documented in publications (see Davie et al, science.1964Sep 18;145 (3638): 1310-2). FXIIa mediated activation of Factor XI (FXI) triggers the intrinsic coagulation pathway. In addition, FXIa can increase clotting in a FXIa-independent manner (see Radcliffe et al, blood.1977, month 10; 50 (4): 611-7; and Puy et al, J Thromb Haemost.2013, month 7; 11 (7): 1341-52. Digital object identifier: 10.1111/jth.12295). Studies in both human and experimental animal models have demonstrated that FXII deficiency extends activated partial prothrombin time (APTT) without adversely affecting hemostasis (see Rennee et al, J Exp Med.2005, 18; 202 (2): 271-81; andfront Med (Lausanne), 2017, 7, 31; 4:121. Digital object identifier: 10.3389/fmed.2017.00121). Pharmacological inhibition of FXIa also prolonged APTT without increasing bleeding (see Worm et al, ann Transl Med.2015, month 10; 3 (17): 247. Digital object identifier: 10.3978/j. Issn. 2305-5839.2015.09.07). These data indicate that inhibiting FXIIa can provide therapeutic effects against thrombosis without inhibiting bleeding. Thus, FXIIa inhibitors are useful in the treatment of a wide range of pre-thrombotic conditions, including Venous Thromboembolism (VTE); cancer-related thrombosis; complications arising from mechanical and biological heart valves, catheters, extracorporeal membrane oxygenation (ECMO), left Ventricular Assist Devices (LVAD), dialysis, cardiopulmonary bypass (CPB); sickle cell disease, arthroplasty, tPA-induced thrombosis, paget-schoerder syndrome (Paget-Schroetter syndrome), and Budd-Chari syndrome (Budd-syndrome). FXIIa inhibitors are useful in the treatment and/or prevention of thrombosis, oedema, and inflammation associated with these conditions.

Contact of the surface of the medical device with blood may cause thrombosis. FXIIa inhibitors may also be useful in the treatment or prevention of thromboembolism by reducing the propensity of devices in contact with blood to coagulate blood. Examples of blood-contacting devices include vascular prostheses, stents, indwelling catheters, external catheters, orthopedic prostheses, cardiac prostheses, and extracorporeal circulation systems.

Preclinical studies have shown that FXIa has shownCausing Stroke and its complications after both ischemic Stroke and hemorrhagic accidents (see Barbieri et al, J Pharmacol Exp Ther.2017, 3 months; 360 (3): 466-475. Digital object identifier: 10.1124/jpeg.116.238493; krupka et al, PLoS One.2016, 27 days; 11 (1): e0146783. Digital object identifier: 10.1371/journ.fine.0146783; leung et al, transl Stroke Res.2012, 9 months; 3 (3): 381-9. Digital object identifier: 10.1007/s 12975-012-0186-5);blood.2017, 4, 20; 129 2280-2290. Digital object identifier: 10.1182/blood-2016-09-740670; and Liu et al, nat med.2011, month 2; 17 206-10. Digital object identifier: 10.1038/nm.2295). Thus, FXIIa inhibition may improve the clinical neurological outcome of treatment of stroke patients.

FXII deficiency has been shown to reduce Apoe ^-/- Atherosclerotic lesion formation in mice (Didiasova et al, cell Signal.2018, month 11; 51:257-265. Digital object identifier: 10.1016/j. Cellsig.2018.08.006). Thus, FXIIa inhibitors are useful in the treatment of atherosclerosis.

FXIa has been shown to activate the complement system directly or indirectly via PKa (Ghebrehiwet et al, immunol Rev.2016, 11 months; 274 (1): 281-289. Digital object identifier: 10.1111/imr. 12469). BK increases complement C3 in the retina, and the increase in complement C3 in the vitreous is associated with DME (Murugesan et al, exp Eye Res.2019, 24 th 7 th; 186:107744. Digital object identifier: 10.1016/j. Exhr.2019.107744). Both FXIa and PKa activate the complement system (see Irmscher et al, J Innate Immun.2018;10 (2): 94-105. Digital object identifier: 10.1159/000484257; and Ghebrehiwet et al, J Exp Med.1981, 3, 1; 153 (3): 665-76).

Phase 2 studies assessing the safety and efficacy of the FXIIa inhibitor CSL312 in covd-19 treatment have been assigned the clinicaltrias gov identifier NCT04409509.Shatzel et al (Res Pract Thromb Haemost,2020, 5/15; 4 (4): 500-505. Digital object identifier: 10.1002/rth 2.12349) are also directed to studying the role of contact systems in COVID-19.

Wyglecka et al ("Coagulation factor XII regulates inflammatory responses in human lungs", european Respiratory Journal 2017:PA339; digital object identifier: 10.1183/1393003. Congress-2017.PA339) relates to the effect of FXII accumulation in the lung of Acute Respiratory Distress Syndrome (ARDS).

Wong et al ("CSL 312, a.novel Anti-FXII Anti-body, blocks FXII-Induced IL-6Production from Primary Non-Diseased and Idiopathic Pulmonary Fibrosis Fibroblasts", american Journal of Respiratory and Critical Care Medicine 2020;201: A6363) report that activated FXII can cause pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis) via direct stimulation of fibroblasts to produce the pro-fibrotic cytokine IL-6.

Et al (The Coagulation Factors Fibrinogen, thrombin, and Factor XII in Inflammatory Disorders-A Systematic Review, front. Immunol., 7.7.26.2018 |https:// doi.org/10.3389/fimmu.2018.01731) are directed to the role of FXII in Rheumatoid Arthritis (RA).

Scheffl et al (Cold-induced urticarial autoinflammatory syndrome related to factor XII activation, nature Communications, volume 11, paper No. 179 (2020)) report that there is a correlation between contact system activation and cytokine-mediated inflammation such as Cold-induced urticaria auto-inflammatory syndrome.

Compounds known as FXIia inhibitors have been described by Rao et al ("Factor XIIa Inhibi tors" WO 2018/093695), hicks et al ("Factor XIIa Inhibitors" WO 2018/093716), brevlow et al ("Aminotriazole immunomodulators for treating autoimmune diseases" WO 2017/123518), ponda et al ("Aminacylind azole immunomodulators for treatment of autoimmune diseases" WO2017/205296 and "Pyranopyrazole and pyrazolopyridine immunomodulato rs for treatment of autoimmune diseases" WO 2019/108565). FXI/FXIIa inhibitors are said to have been described by Nolte et al ("Factor XII inhibitors for the ad ministration with medical procedures comprising contact with artifici al surfaces" WO 2012/120128).

Compounds known as FXIa modulators have been described by et al ("Factor XIIa Inhibitors" WO 2019/211585 and WO 2019/186164). Macrocyclic peptides which are said to be FXIIIa inhibitors have been described by Wilbs et al (Nat Commun 11,3890 (2020). Digital object identifier: 10.1038/s 41467-020-17648-w).

To date, no FXIIa inhibitors have been approved for medical use, and no small molecule FXIIa inhibitors exist in clinical development. Although certain known compounds are known as modulators or inhibitors of FXIIa, these compounds may have limitations such as irreversible or covalent binders, poor selectivity for FXIIa over other related enzymes, or not exhibit pharmacokinetic properties suitable for oral therapy. For example, compounds having acylated reactivity (e.g., acylated aminotriazoles) are typically irreversible covalent binders and are sometimes also unstable in water and/or plasma due to their inherent reactivity. Poor selectivity for FXIIa over other serine proteases (such as thrombin, FXa, FXIa, KLK, plasmin, trypsin) increases the risk of off-target effects, and may be even more so if the inhibitor is a covalent binding agent (i.e., there is typically a higher likelihood of poor selectivity and off-target effects). Thus, there remains a need to develop new FXIIa inhibitors that are not covalent inhibitors and/or have high selectivity for FXIIa, for example, in order to mitigate the risk of non-selectivity and cytotoxicity. In particular, there is a need to develop small molecule FXIIa inhibitors as oral therapies.

In view of the above, there is also a need to develop new FXIIa inhibitors that would be effective in treating a wide range of disorders, particularly in treating vascular oedema; HAE, comprising: (i) HAE type 1, (ii) HAE type 2, and (iii) normal C1 inhibitor HAE (normal C1-Inh HAE); BK-AEnH, including AE-nC1Inh, ACE and tPA induced angioedema; vascular high permeability; stroke, including ischemic stroke and hemorrhagic accidents; retinal edema; diabetic retinopathy; DME; retinal vein occlusion; AMD; neuroinflammation; neuroinflammatory/neurodegenerative disorders such as MS (multiple sclerosis); other neurodegenerative diseases such as Alzheimer's disease, epilepsy and migraine; sepsis; bacterial sepsis; inflammation; allergy; thrombus; thromboembolism caused by the increased tendency of the medical device to coagulate blood by contact with blood; pre-thrombotic conditions, including Disseminated Intravascular Coagulation (DIC), venous Thromboembolism (VTE), cancer-associated thrombosis, complications from mechanical and biological heart valves, complications from catheters, complications from ECMO, complications from LVAD, complications from dialysis, complications from CPB, sickle cell disease, arthroplasty, tPA-induced thrombosis, peck-sch's syndrome, and bujia syndrome; atherosclerosis; covd-19; acute Respiratory Distress Syndrome (ARDS); idiopathic Pulmonary Fibrosis (IPF); rheumatoid Arthritis (RA); and cold-induced urticaria-type autoinflammatory syndrome. In particular, there remains a need to develop new FXIIa inhibitors.

Disclosure of Invention

The present invention relates to a series of inhibitors of factor XIIa (FXIIIa). The compounds of the invention are potentially useful for the treatment of diseases or conditions associated with factor XIIa inhibition. The invention further relates to pharmaceutical compositions of the inhibitors, the use of the compositions as therapeutic agents and methods of treatment using these compositions. The present invention also relates to compounds suitable for use as intermediates in the synthesis of the FXIIa inhibitors of the invention described herein.

In a first aspect the present invention provides a compound of formula (I)

Wherein:

z is a 6-or 5-membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O; or phenyl; or alternatively, the first and second heat exchangers may be,

z is 2-pyridone or 4-pyridone,

x is selected from SO ₂ And CR1R2;

r1 is selected from H, alkyl, alkoxy, OH, halo, and NR13R14; and is also provided with

R2 is selected from H and small alkyl; or (b)

R1 and R2 together with the carbon atom to which they are attached are joined by an alkylene group to form a 3-, 4-or 5-membered saturated ring;

y is selected from NR12, O and CR3R4;

r3 and R4 are independently selected from H and alkyl; or (b)

X is CR1R2 and Y is CR3R4, and R1 and R3 are joined together with the carbon atom to which R1 is attached and the carbon atom to which R3 is attached by an alkylene group to form a 3-, 4-or 5-membered saturated ring; or (b)

X is CR1R2 and Y is NR12, and R1 and R12 are linked together with the carbon atom to which R1 is attached and the nitrogen atom to which R12 is attached through an alkylene group to form a 3-, 4-or 5-membered saturated heterocyclic ring;

b is selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group;

(iii) A 5-to 6-membered non-aromatic heterocyclic ring containing one N ring member, which may be saturated or unsaturated with 1 or 2 double bonds where applicable, wherein the non-aromatic heterocyclic ring is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

(iv) A fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring comprising an aromatic ring fused to a non-aromatic ring, wherein the bicyclic ring optionally comprises one or two N ring members, wherein the fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring may be optionally substituted with 1, 2, or 3 substituents, up to three substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via the 6-membered or 5-membered ring;

n is 0, 1 or 2;

when present, each R5 is independently selected from alkyl, cyclopropyl, alkoxy, halo, OH, CN, (CH) ₂ ) _0-6 COOH and CF ₃ ；

AW-is selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -O-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NH-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NR12-(CH ₂ ) _1-6 -C(＝O)-A、-(CH ₂ ) _0-6 -NH-C(＝O)-(CH ₂ ) _0-6 -A、-C(＝O)NR12-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -C(＝O)-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 - (phenyl) - (CH) ₂ ) _0-6 -A、-NH-SO ₂ -A and-SO ₂ -NH-A；

A is a 4-to 15-membered monocyclic, bicyclic or tricyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

Wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro;

wherein when a is a tricyclic ring system, each of the three rings in the tricyclic ring system is fused, bridged or bolted to at least one of the other rings in the tricyclic ring system;

alkyl is a radical having up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); the alkyl group may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, -NR13R14, -C (=O) OR13, -C (=O) NR13R14, CN, CF ₃ A halo group;

alkyl group ^b Is of up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); alkyl group ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

the small alkyl radical being a radical having up to 4 carbon atoms (C _1- C ₄ ) Or straight-chain saturated hydrocarbons having 3 to 4 carbon atoms (C ₃ -C ₄ ) Branched saturated hydrocarbons of (2); the small alkyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, NR13R14, C (=o) OR13, C (=o) NR13R14, CN, CF ₃ A halo group;

small alkyl group ^b Is of up to 4 carbon atoms (C ₁ -C ₄ ) Or straight-chain saturated hydrocarbons having 3 to 4 carbon atoms (C ₃ -C ₄ ) Branched saturated hydrocarbons of (2); small alkyl group ^b Optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

alkylene is a radical having 1 to 5 carbon atoms (C ₁ -C ₅ ) Is a divalent straight-chain saturated hydrocarbon of (2); the alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl group ^b 、(C ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

aryl is phenyl, biphenyl or naphthyl; aryl groups may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, - (CH) ₂ ) _0-3 -O-heteroaryl ^a Aryl group ^b -O-aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b 、-(CH ₂ ) _0-3 Heteroaryl group ^a 、-C(＝O)OR13、-C(＝O)NR13R14、-(CH ₂ ) _0-3 -NR13R14、OCF ₃ And CF (compact F) ₃ ；

Aryl group ^b Phenyl, biphenyl or naphthyl; aryl group ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN and CF ₃ ；

NaphtheneThe radicals being those having 3 to 6 carbon atoms (C ₃ -C ₆ ) A monocyclic saturated hydrocarbon ring of (2); cycloalkyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl, (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

alkoxy is a radical having 1 to 6 carbon atoms (C ₁ -C ₆ ) O-linked straight-chain hydrocarbons or having 3 to 6 carbon atoms (C ₃ -C ₆ ) O-linked branched hydrocarbons of (2); alkoxy groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: OH, CN, CF ₃ And fluorine;

halo is F, cl, br or I;

heteroaryl is a 5-or 6-membered carbon-containing aromatic ring containing one, two or three ring members selected from N, NR, S and O; heteroaryl groups may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN and CF ₃ ；

Heteroaryl group ^a A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable; heteroaryl group ^a Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ ；

Heteroaryl group ^b A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ ；

Heterocycloalkyl is a non-aromatic carbon-containing monocyclic ring containing 5, 6 or 7 ring members, wherein one or two ring members are independently selected from N, NR, S, SO ₂ And O; wherein the heterocycloalkyl group may beOptionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, and CN;

r8 is independently selected from H, alkyl, cycloalkyl or heterocycloalkyl ^a ；

Heterocycloalkyl group ^a Is a non-aromatic carbon-containing monocyclic ring containing 3, 4, 5 or 6 ring members, wherein at least one ring member is independently selected from N, NR, S and O; heterocycloalkyl group ^a Optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl, (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

r12 is independently selected from H, alkyl or cycloalkyl;

R13 and R14 are independently selected from H, alkyl ^b Aryl group ^b And heteroaryl group ^b Or R13 and R14 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered carbon-containing heterocyclic ring optionally containing another member selected from N, NR, S, SO ₂ And heteroatoms of O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono-or di-substituted with substituents selected from the group consisting of: oxo, alkyl ^b Alkoxy, OH, halo and CF ₃ ；

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic (scalemic) mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof.

Compounds of formula (I) that have been developed as FXIIa inhibitors as mentioned above have unique specific binding sites and require small molecule FXIIa inhibitors. Furthermore, the compounds of formula (I) have been carefully developed to (I) show selectivity for FXIIa over other serine proteases, thus reducing the risk of off-target effects and cytotoxicity, and (ii) have characteristics that may be considered suitable for oral delivery, such as suitable oral availability characteristics. The compounds of formula (I) may also avoid the inclusion of groups related to covalent binding properties, for example groups having acylation reactivity, such as acylated aminotriazoles, and thus may provide compounds that are reversible inhibitors to further reduce the risk of off-target effects and cytotoxicity.

The invention also provides prodrugs of the compounds as defined herein, or pharmaceutically acceptable salts and/or solvates thereof.

The invention also provides an N-oxide of a compound as defined herein, or a prodrug or a pharmaceutically acceptable salt and/or solvate thereof.

It is understood that "pharmaceutically acceptable salts and/or solvates thereof" means "pharmaceutically acceptable salts thereof", "pharmaceutically acceptable solvates thereof" and "pharmaceutically acceptable solvates of salts thereof".

The compounds of the present invention may be provided as a mixture of more than one stereoisomer. When provided as a mixture of stereoisomers, one stereoisomer may be present in a purity of >90% relative to the remaining stereoisomers. More specifically, when provided as a mixture of stereoisomers, one stereoisomer may be present in a purity of >95% relative to the remaining stereoisomers.

It is understood that substituents may be named according to their free non-bonded structure (e.g., piperidine) or according to their bonded structure (e.g., piperidinyl). The purpose is no difference.

It will be appreciated that the compounds of the present invention contain several substituents. When any of these ring substituents is defined more specifically herein, the substituents/optionally present substituents of these groups described above are also applicable unless otherwise indicated. For example B may be heteroaryl ^a It may more specifically be isoquinolinyl. In this case, the isoquinolinyl group may be substituted with a "heteroaryl group ^a "the same way is optionally substituted.

It will be understood that an "alkylene" has two free valences, i.e. it is divalent, meaning that it is capable of bonding twice. For example, when R1 and R2 together with the carbon atom to which they are attached are joined by an alkylene group to form a 4-membered saturated ring, the alkylene group may be-CH ₂ CH ₂ CH ₂ -。

It will be appreciated that the lines drawn from substituents into the ring system represent designated bonds that may be attached to any of the ring atoms that may be substituted. For example, in formula (I), AW-, X, and R5 (when present) may be attached to any of the ring atoms on Z that may be substituted.

It is understood that when n is 0, no R5 substituent is present on Z, and only the AW-and X substituents are attached to Z.

It will be appreciated that when Z is 2-pyridone or 4-pyridone, the pyridone may be in any orientation and substituted at any of the substitutable ring atoms permitted by formula (I).

It is understood that a fused ring system refers to a ring system in which two rings in the ring system share two adjacent atoms (i.e., one common covalent bond). For exampleIs a fused ring system (specifically, a fused bicyclic ring system) that can be considered as an imidazole ring and a piperidine ring sharing a common bond.

It is understood that a bridged ring system refers to a ring system in which two rings share three or more atoms. For exampleIs a bridged ring system (specifically, a bridged bicyclic ring system) that can be considered as a tetrahydrofuran ring and a pyrrolidine ring joined at a bridge and sharing three common atoms.

It is understood that a spiro ring system refers to a ring system in which two rings in the ring system share a common atom. For exampleA spiro ring system (specifically, a spiro-linked bicyclic ring system) that can be considered as a cyclobutane ring and an azetidine ring sharing a common carbon atom.

It is to be understood that the ring system a as defined in formula (I) may be fully saturated or have any degree of unsaturation. For example, the ring system may be fully saturated, partially unsaturated, aromatic, non-aromatic, or have aromatic rings bridged, fused, or spiro to the non-aromatic rings.

It will be appreciated that ring system a may contain non-carbocyclic members, and that these non-carbocyclic members may themselves (as well as or opposite to the carbocyclic members) optionally be substituted, where applicable, with optionally present substituents included in the definition of a.

It will be appreciated that in Y, the heteroaryl group is ^a In the case where the carbon atom on the ring is attached to B, the connection of Y to B may be at heteroaryl ^a Any carbon on the ring, provided that the remainder of the ring remains a heteroaromatic ring. For example, if B is 7-azaindole, the linkage to Y may be at any of the following ring atoms: But not at the nitrogen ring atom: />

It will be appreciated that in Y, the heteroaryl group is ^a Attached at a carbon atom on the ring to B and two adjacent heteroaryl groups ^a Where the ring atoms of the carbon atoms to which Y is attached on the ring are carbon, these adjacent ring atoms may, where applicable, be substituted or unsubstituted as defined in the embodiments or claims. Furthermore, for example, if B is 7-azaindole, the linkage to Y may be at any of the following ring atoms:

but not at the following ring atoms:

it will be appreciated that when any variable (e.g., alkyl) occurs more than once, its definition at each occurrence is independent of each other occurrence.

It is understood that combinations of substituents and variables are permissible only if such combinations result in stable compounds.

As used herein, the term "bradykinin-mediated vascular edema" means hereditary vascular edema and any non-hereditary bradykinin-mediated vascular edema. For example, "bradykinin-mediated angioedema" encompasses hereditary angioedema and acute bradykinin-mediated angioedema of unknown origin.

As used herein, the term "hereditary angioedema" means any bradykinin-mediated angioedema caused by genetic dysfunction, defect or mutation. Thus, the term "HAE" includes at least HAE type 1, HAE type 2 and normal C1 inhibitor HAE (normal C1-Inh HAE).

Certain preferred subformulae of compounds of formula (I) include compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id) and formula (Ie), as indicated below:

/>

z may be a 6-or 5-membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O; or phenyl; or Z may be 2-pyridone or 4-pyridone. More specifically, Z may be selected from phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 2-pyridone, and 4-pyridone.

Z may be 2-pyridone or 4-pyridone. Z may be 2-pyridone. Z may be 4-pyridone.

Z is a 6-or 5-membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O; or phenyl. More specifically, Z may be selected from phenyl, thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.

Z may be a 6-or 5-membered heteroaromatic ring containing 1 or 2 ring members independently selected from N and S; or phenyl. More specifically, Z may be selected from phenyl, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, pyridine, pyridazine, pyrimidine and pyrazine.

Z may be a 6 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N; or phenyl; or Z may be 2-pyridone or 4-pyridone. More specifically, Z may be selected from phenyl, pyridine, pyridazine, pyrimidine, pyrazine, triazine, 2-pyridone, and 4-pyridone.

Z may be a 6 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N. More specifically, Z may be selected from pyridine, pyridazine, pyrimidine, pyrazine and triazine.

Z may be a 6-or 5-membered heteroaromatic ring containing 1 or 2 ring members which are N; or phenyl. More specifically, Z may be selected from phenyl, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine and pyrazine. Preferably, Z may be selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole. Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole. More preferably, Z is selected from phenyl, pyrimidine and pyridine.

Z may be phenyl.

Z may be a 5 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O. More specifically, Z may be selected from thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole and thiadiazole.

X may be selected from SO ₂ And CR1R2.X may be SO ₂ . When X is SO ₂ When Y may be NH. Preferably, X is CR1R2.

R1 may be selected from H, alkyl, alkoxy, OH, halo and NR13R 14. R1 may be selected from H and alkyl. R1 may be selected from H, methyl and CH (CH) ₂ F) A. The invention relates to a method for producing a fibre-reinforced plastic composite Preferably, R1 is H.

R2 may be selected from H and small alkyl groups. R2 may be selected from H and methyl. Preferably, R2 is H.

Alternatively, R1 and R2 together with the carbon atom to which they are attached may be joined by an alkylene group to form a 3-, 4-or 5-membered saturated ring. Preferably, R1 and R2 together with the carbon atom to which they are attached are joined by an alkylene group to form a 3-or 4-membered saturated ring.

Y may be selected from NR12, O and CR3R4.Y is selected from NH, N (alkyl), N (cycloalkyl), O, CH ₂ CH (alkyl) and C (alkyl). Y is selected from NH, N (CH) ₃ ) O and CH ₂ . Y may be selected from NH and N (CH) ₃ ). Preferably, Y is NH.

Alternatively, X may be CR1R2 and Y may be CR3R4, and R1 and R3 together with the carbon atom to which R1 is attached and the carbon atom to which R3 is attached may form a 3-, 4-, or 5-membered saturated ring through alkylene linkage. For example, X may be CR1R2 and Y may be CR3R4, and R1 and R3 together with the carbon atom to which R1 is attached and the carbon atom to which R3 is attached may form a 3-membered saturated ring through alkylene linkage. For example, X may be CR1R2 and Y may be CR3R4, and R1 and R3 together with the carbon atom to which R1 is attached and the carbon atom to which R3 is attached may form a 4-membered saturated ring through alkylene linkage. For example, X may be CR1R2 and Y may be CR3R4, and R1 and R3 together with the carbon atom to which R1 is attached and the carbon atom to which R3 is attached may form a 5 membered saturated ring through alkylene linkage.

R3 and R4 may be independently selected from H and alkyl. Preferably, at least one of R3 and R4 is H. More preferably, R3 and R4 are both H.

Alternatively, X may be CR1R2 and Y may be NR12, and R1 and R12 together with the carbon atom to which R1 is attached and the nitrogen atom to which R12 is attached may be linked through an alkylene group to form a 3-, 4-, or 5-membered saturated heterocyclic ring. For example, X may be CR1R2 and Y may be NR12, and R1 and R12 together with the carbon atom to which R1 is attached and the nitrogen atom to which R12 is attached may be linked through an alkylene group to form a 3-membered saturated heterocyclic ring. For example, X may be CR1R2 and Y may be NR12, and R1 and R12 together with the carbon atom to which R1 is attached and the nitrogen atom to which R12 is attached may be linked through an alkylene group to form a 4-membered saturated heterocyclic ring. For example, X may be CR1R2 and Y may be NR12, and R1 and R12 together with the carbon atom to which R1 is attached and the nitrogen atom to which R12 is attached may be linked through an alkylene group to form a 5-membered saturated heterocyclic ring.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H and Y is NH. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H and Y is NH.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H and Y is NH. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H and Y is NH.

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H and Y is NH.

B may be selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group;

(iv) A fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring comprising an aromatic ring fused to a non-aromatic ring, wherein the bicyclic ring optionally comprises one or two N ring members, wherein the fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring may be optionally substituted with 1, 2, or 3 substituents, up to three substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via the 6-membered or 5-membered ring.

B may be selected from:

(i) Heteroaryl group ^a ；

(ii) A 5-to 6-membered non-aromatic heterocyclic ring containing one N ring member, which may be saturated or unsaturated with 1 or 2 double bonds where applicable, wherein the non-aromatic heterocyclic ring is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

(iii) A fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring comprising an aromatic ring fused to a non-aromatic ring, wherein the bicyclic ring optionally comprises one or two N ring members, wherein the fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring may be optionally substituted with 1, 2, or 3 substituents, up to three substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via the 6-membered or 5-membered ring.

B may be selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group; and

(iii) A 5-to 6-membered non-aromatic heterocyclic ring containing one N ring member, which may be saturated or unsaturated with 1 or 2 double bonds where applicable, wherein the non-aromatic heterocyclic ring is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ 。

Specifically, B is selected from:

(i) Heteroaryl group ^a The method comprises the steps of carrying out a first treatment on the surface of the And

(ii) A 5-to 6-membered non-aromatic heterocyclic ring containing one N ring member, which may be saturated or unsaturated with 1 or 2 double bonds where applicable, wherein the non-aromatic heterocyclic ring is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ 。

Preferably, B is heteroaryl ^a . Preferably, when B is heteroaryl ^a When B is preferably NH ₂ Substituted, and optionally as heteroaryl ^a Substituted with 1 or 2 other substituents.

When B is heteroaryl ^a When B may be a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O where applicable; wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkaneOxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O where applicable; wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, optionally as heteroaryl ^a Is substituted. B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O where applicable, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O where applicable, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be a 9 or 10 membered bicyclic aromatic ring containing 1 or 2 rings independently selected from N, NR, S and O, where applicable, optionally as heteroaryl ^a Is substituted. B may be a 9-or 10-membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O where applicable, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be a 9-or 10-membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O where applicable, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be a 9-or 10-membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N and NR12, where applicable, optionally as heteroaryl ^a Is substituted. B may be a 9-or 10-membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N and NR12 where possible, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be a 9-or 10-membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N and NR12 where possible, wherein B may be optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When Y is preferably heteroaryl ^a The carbon atom on the ring is attached to B. In particular, when B is heteroaryl ^a When Y is preferably heteroaryl ^a At a carbon atom on the ring, to B, and two are adjacent to the heteroaryl group ^a The ring atoms of the carbon atoms to which Y is attached on the ring are all carbon.

When B is heteroaryl ^a When B is preferably selected from: isoquinolinyl radicalOptionally as heteroaryl ^a Is substituted; 6-azaindolesBase->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. B may be isoquinolinyl->Optionally as heteroaryl ^a Is substituted. B may be 6-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be 7-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

More specifically, B is selected from: isoquinolinyl selected fromOptionally as heteroaryl ^a Is substituted; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. B may be isoquinolinyl, selected from B may be 6-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be 7-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

More specifically, B is selected from: isoquinolinyl radicalBy NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl- >Optionally as heteroaryl ^a Is substituted; 7-azaindolylOptionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. B may be isoquinolinyl->By NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be 6-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be 7-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

More specifically, B is selected from: isoquinolinyl selected fromBy NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. B may be isoquinolyl selected from->By NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be 6-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be 7-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

More specifically, B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. B may be NH at position 1 ₂ Substituted isoquinolinyl->Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be 6-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be 7-azaindolylOptionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

Preferably, when B is heteroaryl ^a When B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted.

Specifically, B may be NH at position 1 ₂ Substituted isoquinolinyl selected from Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be NH at position 1 ₂ Substituted isoquinolinylOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be NH at position 1 ₂ Substituted isoquinolinyl->Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents. B may be 6-azaindolylOptionally as heteroaryl ^a Is substituted. B may be 7-azaindolyl +.>Optionally as heteroaryl ^a Is substituted. B may be pyridinyl->Optionally as heteroaryl ^a Is substituted.

When B is heteroaryl ^a When B is preferably isoquinolinyl, optionally as heteroaryl ^a Is substituted. B is preferably isoquinolinyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B is preferably isoquinolinyl optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is isoquinolinyl, B may be selected fromOptionally as heteroaryl ^a Is substituted. B is selected from-> Optionally 1, 2 or 3 are independently selected from the group consisting ofIs substituted by a substituent of (a): alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B is selected from->Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is isoquinolinyl, B can beOptionally as heteroaryl ^a Is substituted. B may beOptionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may beOptionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is isoquinolinyl, B can beOptionally as heteroaryl ^a Is substituted. B may beOptionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group,Alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may beOptionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B is preferably NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents. B is preferably NH ₂ Isoquinolinyl substituted and optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B is preferably NH ₂ Isoquinolinyl substituted and optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is NH ₂ In the case of substituted isoquinolinyl, B may be selected from Optionally as heteroaryl ^a Substituted with 1 or 2 other substituents. B is selected from->Optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B can be selected fromOptionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is NH ₂ In the case of substituted isoquinolinyl, B may beOptionally as heteroaryl ^a Substituted with 1 or 2 other substituents. B may be->Optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be- >Optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is NH ₂ In the case of substituted isoquinolinyl, B may beOptionally as heteroaryl ^a Substituted with 1 or 2 other substituents. B may be->Optionally 1 or 2 of them independently selected fromHe substituents are substituted: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be->Optionally substituted with 1 or 2 other substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is NH ₂ In the case of substituted isoquinolinyl, B may be selected from Optionally substituted with another substituent selected from halo. />

When B is NH ₂ In the case of substituted isoquinolinyl, B may beOptionally substituted with another substituent selected from halo.

When B is NH ₂ In the case of substituted isoquinolinyl, B may be selected from Optionally substituted at the carbon marked 4 with another substituent selected from halo.

When B is NH ₂ In the case of substituted isoquinolinyl, B may beOptionally substituted at the carbon marked 4 with another substituent selected from halo.

Preferably, B is selected from:

when B is heteroaryl ^a When B may be a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B may be a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ A halogen group,Aryl group ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B may be a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be a 9-or 10-membered bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable, substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be quinolinyl or isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ CN, halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be quinolinyl or isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b 、-C(＝O)OR12、-C(＝O)NR13R14 and CF ₃ . B may be quinolinyl or isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ . When B is heteroaryl ^a When B may be isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ CN, halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ . B may be isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b And CF (compact F) ₃ 。

When B is heteroaryl ^a When B may be isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B may be isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from alkoxy.

When B is heteroaryl ^a When B may be isoquinolinyl substituted with 1, 2 or 3 substituents selected from-OMe.

When B is heteroaryl ^a When B is isoquinolinyl substituted with-OMe. B may be selected from:substituted at one of the carbons labeled 3, 4, 5, 7 or 8 with-OMe; and->Substituted at one of the carbons labeled 3, 4, 6, 7 or 8 with-OMe. B is selected from->Substituted at carbon labeled 8 with-OMe. B may be->Substituted at one of the carbons labeled 3, 4, 6, 7 or 8 with-OMe. B may be->Substituted at carbon labeled 8 with-OMe. B may beSubstituted at one of the carbons labeled 3, 4, 5, 7 or 8 with-OMe. B may be->Substituted at carbon labeled 8 with-OMe.

When B is heteroaryl ^a When B is isoquinolinyl substituted with-Me. B may be selected from:substituted at one of the carbons labeled 3, 4, 5, 7 or 8 with-Me; and->Substituted at one of the carbons labeled 3, 4, 6, 7 or 8 with-Me. B is selected from->Substituted at the carbon labeled 8 with-Me. B may be- >In the marks 3, 4, 6, 7 or8 is substituted at one of the carbons by-Me. B may be->Substituted at the carbon labeled 8 with-Me. B may beSubstituted at one of the carbons labeled 3, 4, 5, 7 or 8 with-Me. B may beSubstituted at the carbon labeled 8 with-Me.

When B is heteroaryl ^a When B may be a 9 membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O; wherein B is optionally as heteroaryl ^a Is substituted.

When B is heteroaryl ^a When B may be a 9 membered bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O; wherein B is substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ The method comprises the steps of carrying out a first treatment on the surface of the Wherein the substituents on B are attached only to carbon ring members.

Preferably, when B is heteroaryl ^a When applicable, the substituents optionally present on B are independently selected from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

When B is heteroaryl ^a When B is selected from

/>

When B is heteroaryl ^a When B is selected from

/>

Preferably, B is selected from:

/>

Preferably, B is selected from:

b may be aryl. B may be phenyl or naphthyl, wherein B may be optionally substituted as aryl. When B is aryl, preferably B is phenyl, wherein B may be optionally substituted as aryl.

B may be selected from:

b may be selected from:

b may be a 5-to 6-membered non-aromatic heterocycle containing one N ring member, which may be saturated or have 1 or 2 double bonds without saturation where possible, wherein the non-aromatic heterocycle is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ 。

B may be pyrrolidine optionally substituted with 1, 2 or 3 substituents independently selected from: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ 。

B may be optionally substituted with 1 aryl group ^b Substituted pyrrolidines.

B may be a pyridone having 2 double bonds but being unsaturated, which may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ 。

B may be an unsaturated pyridone having 2 double bonds, which is substituted with two alkyl groups.

B may be selected from:

b may be a fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring containing an aromatic ring fused to a non-aromatic ring, wherein the bicyclic ring optionally contains one or two N ring members, wherein the fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring may be optionally substituted with 1, 2, or 3 substituents, up to three substituents independently selected from: alkyl group, Alkoxy, OH, OCF ₃ Halo, oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via a 6-membered or 5-membered ring.

B may be selected from:

b may be selected from:

preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is heteroaryl ^a 。

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is heteroaryl ^a . More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; and B is heteroaryl ^a 。

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; and B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected from->Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is optionally as heteroaryl ^a Substituted isoquinolinyl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is optionally as heteroaryl ^a Substituted isoquinolinyl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; and B is optionally as heteroaryl ^a Substituted isoquinolinyl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; and B is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; and B is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents.

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; and B is heteroaryl ^a . More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; and B is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further by 1 or 2A substituent group; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; and B is optionally as heteroaryl ^a Substituted isoquinolinyl. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; and B is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents.

When B is heteroaryl ^a And is a 9 membered bicyclic aromatic ring containing a 5 membered ring fused to a 6 membered ring, and when B is connected to Y via a 6 membered ring, the 9 membered bicyclic aromatic ring preferably contains 1 or 2 ring members independently selected from N, NR, S and O; and e.g. heteroaryl ^a Optionally substituted.

When B is heteroaryl ^a And is selected from 6-azaindolylAnd 7-azaindolyl +.>When B is preferably as heteroaryl ^a Optionally substituted, and any optionally present substituents are located, where applicable, at any ring member other than the ring member labeled # or members. It is to be understood that the ring member labeled # is the ring member shown as "NH", i.e., nitrogen as part of the fused 5-membered pyrrole ring 。

n may be 0, 1 or 2.n may be 0.n may be 1.n may be 2.n may be 1 or 2. Preferably n is 0 or 1.

When n is 0, R5 is absent.

When present (i.e., when n is not 0), R5 may be independently selected from alkyl, cyclopropyl, alkoxy, halo, OH, CN, (CH) ₂ ) _0-6 COOH and CF ₃ 。

R5 may be independently selected from alkyl, alkoxy, halo, OH, CN, (CH) ₂ ) _0-6 COOH and CF ₃ 。

R5 can be independently selected from CH ₃ 、OH、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ 、F、Cl、(CH ₂ ) _0-6 COOH、CN、CH ₂ F、CHF ₂ 、CH ₂ OCH ₃ And

r5 may be independently selected from alkyl, alkoxy, halo, CN and CF ₃ 。

R5 may be independently selected from the group consisting of small alkyl, O- (small alkyl), halogen, CN and CF ₃ 。

Preferably, R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, R5 is independently selected from OCH ₃ 、CF ₃ F and Cl.

R5 may be CH ₃ . R5 may be CH ₂ OH. R5 can be OCH ₃ . R5 may be OiPr. R5 may be CF ₃ . R5 may be F. R5 may be CN. R5 may be Cl.

When Z is a 6 membered ring, R5 is preferably ortho or meta substituted with respect to the X substituent.

Preferably, n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 isH is formed; r2 is H; y is NH; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ 、FCN and Cl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionalEarth, e.g. heteroaryl ^a Is substituted; 7-azaindolyl- >Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl.

AW-may be selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -O-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NH-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NR12-(CH ₂ ) _1-6 -C(＝O)-A、-(CH ₂ ) _0-6 -NH-C(＝O)-(CH ₂ ) _0-6 -A、-C(＝O)NR12-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -C(＝O)-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 - (phenyl) - (CH) ₂ ) _0-6 -A、-NH-SO ₂ -A and-SO ₂ -NH-A。

When A-is-C (=O) NR12- (CH) ₂ ) _0-6 -A or-(CH ₂ ) _0-6 -C(＝O)-(CH ₂ ) _0-6 At-a, AW-is preferably bonded at a carbocycle member of Z.

AW-may be selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-5 -A、-(CH ₂ ) _0-5 -O-(CH ₂ ) _0-5 -A、-(CH ₂ ) _0-5 -NH-(CH ₂ ) _0-5 -A、-(CH ₂ ) _0-5 -NR12-(CH ₂ ) _1-5 -C(＝O)-A、-(CH ₂ ) _0-5 -NH-C(＝O)-(CH ₂ ) _0-5 -A、-C(＝O)NR12-(CH ₂ ) _0-5 -A、-(CH ₂ ) _0-5 -C(＝O)-(CH ₂ ) _0-5 -A、-(CH ₂ ) _0-5 - (phenyl) - (CH) ₂ ) _0-5 -A、-NH-SO ₂ -A and-SO ₂ -NH-A。

AW-may be selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-4 -A、-(CH ₂ ) _0-4 -O-(CH ₂ ) _0-4 -A、-(CH ₂ ) _0-4 -NH-(CH ₂ ) _0-4 -A、-(CH ₂ ) _0-4 -NR12-(CH ₂ ) _1-4 -C(＝O)-A、-(CH ₂ ) _0-4 -NH-C(＝O)-(CH ₂ ) _0-4 -A、-C(＝O)NR12-(CH ₂ ) _0-4 -A、-(CH ₂ ) _0-4 -C(＝O)-(CH ₂ ) _0-4 -A、-(CH ₂ ) _0-4 - (phenyl) - (CH) ₂ ) _0-4 -A、-NH-SO ₂ -A and-SO ₂ -NH-A。

AW-may be selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C(＝O)-A、-(CH ₂ ) _0-3 -NH-C(＝O)-(CH ₂ ) _0-3 -A、-C(＝O)NR12-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -C(＝O)-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 - (phenyl) - (CH) ₂ ) _0-3 -A、-NH-SO ₂ -A and-SO ₂ -NH-A。

Preferably, AW-may be selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -A。

More specifically, AW-may be selected from:

-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A and- (CH) ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C(＝O)-A。

More preferably, AW is selected from the group consisting of-O- (CH) ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A、-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C(＝O)-A。

More specifically, AW is selected from the group consisting of-A, -OCH ₂ -A、-CH ₂ O-A、-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C(＝O)-A。

A may be a 4-to 15-membered monocyclic, bicyclic or tricyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when A is a bicyclic ring systemThe bicyclic ring system is fused, bridged or spiro; wherein when a is a tricyclic ring system, each of the three rings in the tricyclic ring system is fused, bridged or bolted to at least one of the other rings in the tricyclic ring system.

A may be a 4-to 15-membered monocyclic, bicyclic or tricyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from the group consisting of: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro; wherein when a is a tricyclic ring system, each of the three rings in the tricyclic ring system is fused, bridged or bolted to at least one of the other rings in the tricyclic ring system.

A may be a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

A may be a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from the following, where applicable: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. A may be a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from alkyl and cycloalkyl, where applicable; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. A may be a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one other ring member independently selected from N, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from alkyl and cycloalkyl, where applicable; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

A may be a 4-to 7-membered monocyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from the group consisting of: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN. A may be a 4-to 7-membered monocyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from alkyl and cycloalkyl, where applicable. A may be a 4-to 7-membered monocyclic ring system containing one N ring member and optionally one other ring member independently selected from N, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from alkyl and cycloalkyl, where applicable.

A is a 6 membered monocyclic ring system containing one N ring member, wherein said ring system is substituted with 1 substituent selected from alkyl and cycloalkyl. More preferably, a is a 6 membered monocyclic ring system containing one N ring member, wherein said ring system is substituted with 1 alkyl substituent selected from the group consisting of methyl, ethyl, isopropyl and cyclopropyl. Preferably, a 6 membered monocyclic ring system containing one N ring member is bonded to W at the carbon para to the nitrogen.

A may be a 4-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein the ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein the bicyclic ring system is fused, bridged or spiro-linked.

A may be a 6-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein the ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein the bicyclic ring system is fused, bridged or spiro-linked.

A may be a fused 6-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, wherein the fused ring system consists of an aromatic ring fused to a non-aromatic ring, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN. A may be a fused 6-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, Wherein the fused ring system consists of aromatic rings fused to non-aromatic rings, optionally wherein the ring system is optionally substituted with 1, 2, 3 or 4 groups independently selected from alkyl and CF, where applicable ₃ Is substituted by a substituent of (a).

A may be a fused 6-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, wherein the fused ring system consists of a 5-membered aromatic ring fused with a 6-membered non-aromatic ring, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN. A may be a fused 6-to 12-membered bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, wherein the fused ring system consists of a 5-membered aromatic ring fused with a 6-membered non-aromatic ring, optionally wherein the ring system is independently selected from alkyl and CF, where applicable, 1, 2, 3 or 4 ₃ Is substituted by a substituent of (a).

A may be selected from:

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a may be selected from:

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a may be selected from:

Preferably, a is selected from:

preferably, a is selected from:

more preferably, a is selected from:

preferably, AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

More preferably, AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; AW-is selected from:

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when A is doubleWhen ring systems, the bicyclic ring systems are fused, bridged or spiro-linked.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and A is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein the ring system is 1, 2, 3 or 4, where applicable Each independently selected from the following substituents: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and A is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other rings independently selected from N, O and SA member, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from the following, where applicable: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and A is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is optionally substituted with 1, 2, 3 or 4 of the following independently selected fromSubstitution of substituents: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected from Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and is also provided withA is a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected from Optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when A is a bicyclic ringWhen ring systems, the bicyclic ring systems are fused, bridged or spiro.

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when A is a bicyclic ring system, the bicyclic ringThe system is fused, bridged or bolted.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and A is a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally oneTwo or three other ring members independently selected from N, O and S, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 isH is formed; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl- >Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl;AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is of formula (Ia), formula (Ib), formula (Ic), formula (Id) Or a compound of formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; AW-is selected from:

Preferably, n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and A is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is independently selected from 1, 2, 3 or 4, where applicable The following substituents are substituted: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r is R2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; and B is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole;x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a And n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the n is 0 or 1; and R5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolylOptionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl- >Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from: />

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl, AW-selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and A is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is independently selected from 1, 2, 3 or 4, where applicable, to The following substituents are substituted: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl, AW-selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

More preferably, Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and A is a 4-to 12-membered monocyclic or bicyclic ring systemA system comprising one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein the ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, Z is selected from phenyl, pyrimidine and pyridine; x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

Preferably, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is heteroaryl ^a The method comprises the steps of carrying out a first treatment on the surface of the n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-selectionSelf-contained:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CHR12)-A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -O-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NH-(CH ₂ ) _0-3 -A、-(CH ₂ ) _0-3 -NR12-(CH ₂ ) _1-3 -C (=o) -a and-C (=o) NR12- (CH) ₂ ) _0-3 -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR 13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is selected from: is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; 6-azaindolyl->Optionally as heteroaryl ^a Is substituted; 7-azaindolyl->Optionally as heteroaryl ^a Is substituted; and pyridyl->Optionally as heteroaryl ^a Is substituted; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and A is 4 to 1 memberedA 2-membered mono-or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is optionally as heteroaryl ^a Substituted isoquinolinyl; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

-O-(CH(CH ₃ ))-A、-A、-OCH ₂ -A、-CH ₂ O-A、-C(＝O)-(CH ₂ )-A-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C (=o) -a; and a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ CN; wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked. More specifically, the compound of formula (I) is a compound of formula (Ia), formula (Ib), formula (Ic), formula (Id) or formula (Ie); x is CR1R2; r1 is H; r2 is H; y is NH; b is NH ₂ Substituted and optionally e.g. heteroaryl ^a Isoquinolinyl substituted with 1 or 2 other substituents; n is 0 or 1; r5 is independently selected from CH ₃ 、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ F, CN and Cl; AW-is selected from:

For the compounds provided in the following tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10, where stereochemistry is indicated, the compounds are intended to encompass all possible stereoisomers thereof.

Accordingly, the present invention provides compounds of the following tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10, and pharmaceutically acceptable salts and/or solvates thereof. Thus, the present invention also provides stereoisomers of the compounds in tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10 below, and pharmaceutically acceptable salts and/or solvates thereof.

Accordingly, the present invention provides the compounds of tables 1a, 2a, 3, 4a, 5a, 6, 7 and 8a, and pharmaceutically acceptable salts and/or solvates thereof. Thus, the present invention also provides stereoisomers of the compounds in tables 1a, 2a, 3, 4a, 5a, 6, 7 and 8a below, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 1a, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 1a, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 1b, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 1b, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 2a, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 2a, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 2b, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 2b, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 3, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 3, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 4a, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 4a, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 4b, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 4b, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 5a, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 5a, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 5b, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 5b, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 6, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 6, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 7, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 7, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 8a, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 8a, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 8b, and pharmaceutically acceptable salts and/or solvates thereof. The present invention also provides stereoisomers of the compounds selected from table 8b, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 8c, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 8c, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 9, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 9, and pharmaceutically acceptable salts and/or solvates thereof.

The present invention provides compounds selected from table 10, and pharmaceutically acceptable salts and/or solvates thereof. The invention also provides stereoisomers of the compounds selected from table 10, and pharmaceutically acceptable salts and/or solvates thereof.

It will be appreciated that when the compounds in tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10 below are read out, the substituents are read out from left to right. Example compound 2185 of Table 2a has Q ₁ The group:and Q ₂ Radical "OCH ₂ ". Thus Q ₁ The radical being attached to Q ₂ Radical "OCH ₂ "O" in "is as follows: />

TABLE 1a

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TABLE 1b

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TABLE 2a

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TABLE 2b

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TABLE 3 Table 3

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TABLE 4a

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TABLE 4b

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TABLE 5a

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TABLE 5b

TABLE 6

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TABLE 7

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TABLE 8a

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TABLE 8b

TABLE 8c

TABLE 9

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Table 10

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Preferably, the compound of formula (I) is a compound selected from the following example numbers: 1033. the pharmaceutically acceptable salts of 1243, 1251, 1282, 1295, 1299, 1303, 1305, 1309, 1311, 1314, 1316, 1319, 1342, 1344, 1345, 2178, 2197, 2199, 2201, 2256, 4261, 4267, 4268, 4270, 4285, 4298, 4430, 4446, 9005, 9007, 9008, 1002, 1005, 1006, 1009, 1010, 1012, 1013, 1016, 1023, 1024, 1027, 1029, 1042, 1044, 1193, 1195, 1202, 1279, 1300, 1301, 1313, 1321, 1331, 1333, 217, 2185, 2186, 2191, 2192, 2198, 2202, 2213, 2216, 2254, 2257, 4260, 4265, 4269, 4277, 4278, 4284, 4497, 4299, 4400, 443, 9, 19, 4320, 448, 4412, 4414, 34, 37, 4443, 4445, 4450 and 4450.

Preferably, the compound of formula (I) is a compound selected from the following example numbers: 1033. 2178, 2197, 2199, 2201, 4261, 4267, 4268, 4270, 4285, 4298, 4430, 1002, 1005, 1006, 1009, 1010, 1012, 1013, 1016, 1023, 1024, 1027, 1029, 1042, 1044, 2177, 2185, 2186, 2191, 2192, 2198, 2202, 2212, 2213, 2216, 4260, 4265, 4269, 4277, 4278, 4284, 4297, 4299, 4300, 4303, 4309, 4319, 4320, 4408, 4412, 4414, 4424 and 4431, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1202. 1096, 1274, 1219, 1278, 1251, 1282, 1299, 1305, 1309, 9005, 1311, 1314, 2256, 4265, 2185, 2186, 2191, 2192, 2177, 1010, 1013, 2197, 4260, 4261, 2199, 2198, 1027, 1029, 4267, 2212, 4298, 4300, 4320, 4319, 4430, 4307 and 4309, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 4265. 2185, 2186, 2191, 2192, 2177, 1010, 1013, 2197, 4260, 4261, 2199, 2198, 1027, 1029, 4267, 2212, 4298, 4300, 4320, 4319, 4430, 4307, and 4309, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1202. 1096, 1274, 1219, 1278, 1251, 1282, 1299, 1305, 1309, 9005, 1311, 1314 and 2256, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1033. 1243, 1251, 1282, 1295, 1299, 1303, 1305, 1309, 1311, 1314, 1316, 1319, 1342, 1344, 1345, 2178, 2197, 2199, 2201, 2256, 4261, 4267, 4268, 4270, 4285, 4298, 4430, 4446, 9005, 9007 and 9008, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1033. 2178, 2197, 2199, 2201, 4261, 4267, 4268, 4270, 4285, 4298 and 4430, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1029. 1243, 1274, 1277, 1282, 1305, 2186, 2191, 2197, 2212, 4260, 4268, 4299, and 4301, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 4292. 2186, 2191, 2197, 4260 and 4268, and pharmaceutically acceptable salts and/or solvates thereof.

More preferably, the compound of formula (I) is a compound selected from the following example numbers: 1029. 2186, 2191, 2197, 4260 and 4268, and pharmaceutically acceptable salts and/or solvates thereof.

Therapeutic applications

As mentioned above, the compounds of the invention (or pharmaceutically acceptable salts and/or solvates thereof) and pharmaceutical compositions comprising said compounds (or pharmaceutically acceptable salts and/or solvates thereof) are FXIIa inhibitors. Thus, it is useful in the treatment of disease states in which FXIIa is a causative agent.

Accordingly, the present invention provides a compound of the present invention (or a pharmaceutically acceptable salt and/or solvate thereof), or a pharmaceutical composition comprising a compound of the present invention (or a pharmaceutically acceptable salt and/or solvate thereof), for use in medicine.

The invention also provides the use of a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof) or a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof) for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition associated with FXIIa activity.

The invention also provides a method of treating a disease or condition associated with FXIIa activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof) or a pharmaceutical composition comprising a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof).

As discussed above, FXIIa may mediate conversion of plasma prekallikrein to plasma kallikrein. Plasma kallikrein can then cause cleavage of high molecular weight kininogens to produce bradykinin, a potent inflammatory hormone. Inhibition of FXIIa has the potential to inhibit (or even prevent) plasma kallikrein production. Thus, the disease or condition associated with FXIIa activity may be bradykinin mediated angioedema.

Bradykinin-mediated angioedema may be non-hereditary. For example, the non-hereditary bradykinin mediated angioedema may be selected from non-hereditary angioedema with normal C1 inhibitor (AE-nC 1 Inh), which may be environmental, hormonal, or drug induced; acquired angioedema; vascular edema associated with allergy; angiotensin converting enzyme (ACE or ACE) inhibitor-induced angioedema; dipeptidyl peptidase-4 inhibitor induced angioedema; and tPA-induced angioedema (tissue plasminogen activator-induced angioedema).

Alternatively, and preferably, bradykinin mediated vascular edema may be hereditary vascular edema (HAE), which is vascular edema caused by inherited dysfunctions/defects/mutations. Types of HAE that can be treated with the compounds according to the invention include HAE type 1, HAE type 2 and normal C1 inhibitor HAE (normal C1Inh HAE).

Diseases or conditions associated with FXIIa activity may be selected from vascular hyperpermeability, stroke (including ischemic stroke and hemorrhagic accidents); retinal edema; diabetic retinopathy; DME; retinal vein occlusion; and AMD. These conditions may also be bradykinin mediated.

As discussed above, FXIIa can activate FXIa to cause a coagulation cascade. Thrombosis disorders are associated with this cascade. Thus, the disease or condition associated with FXIIa activity may be a thrombotic disorder. More specifically, the thrombotic disorder may be thrombosis; thromboembolism caused by the increased tendency of the medical device to coagulate blood by contact with blood; pre-thrombotic conditions such as Disseminated Intravascular Coagulation (DIC), venous Thromboembolism (VTE), cancer-associated thrombosis, complications arising from mechanical and biological heart valves, complications arising from catheters, complications arising from ECMO, complications arising from LVAD, complications arising from dialysis, complications arising from CPB, sickle cell disease, arthroplasty, tPA-induced thrombosis, peck-sch's syndrome, and bujia syndrome; atherosclerosis; covd-19; acute Respiratory Distress Syndrome (ARDS); idiopathic Pulmonary Fibrosis (IPF); rheumatoid Arthritis (RA); and cold-induced urticaria-type autoinflammatory syndrome.

Contact of the surface of the medical device with blood may cause thrombosis. The compounds (or pharmaceutically acceptable salts and/or solvates thereof) and pharmaceutical compositions of the present invention may be coated on the surface of the device in contact with blood to reduce the risk of the device causing thrombosis. For example, it may reduce the tendency of these devices to coagulate blood and thus cause thrombosis. Examples of blood-contacting devices include vascular prostheses, stents, indwelling catheters, external catheters, orthopedic prostheses, cardiac prostheses, and extracorporeal circulation systems.

Other disease conditions in which FXIIa is a causative agent include: neuroinflammation; neuroinflammatory/neurodegenerative disorders such as MS (multiple sclerosis); other neurodegenerative diseases such as Alzheimer's disease, epilepsy and migraine; sepsis; bacterial sepsis; inflammation; vascular high permeability; and allergies.

Combination therapy

The compounds of the invention (or pharmaceutically acceptable salts and/or solvates thereof) may be administered in combination with other therapeutic agents. Suitable combination therapies include any of the compounds of the invention (or pharmaceutically acceptable salts and/or solvates thereof) in combination with one or more agents selected from the group consisting of agents that inhibit Platelet Derived Growth Factor (PDGF), endothelial growth factor (VEGF), integrin α5β1, steroids, other agents that inhibit FXIIa, and other inhibitors of inflammation.

Some specific examples of therapeutic agents that may be combined with the compounds of the invention include EP2281885A1 and s.patel at Retina,2009, 6; 29 (journal 6) those therapeutic agents disclosed in S45-8.

Other suitable combination therapies include a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof) in combination with one or more agents selected from agents for the treatment of HAE (as generally defined herein), e.g., bradykinin B2 antagonists such as icatibant The method comprises the steps of carrying out a first treatment on the surface of the Plasma kallikrein inhibitors, such as Ai Kala peptide (ecallantide)>Lenali mab (lanadelumab)/(lanadelumab)>And Bei Luosi he (berotralstat) (ORLADEYO ^TM ) The method comprises the steps of carrying out a first treatment on the surface of the Or C1 esterase inhibitors, such as->And->Andand->

Other suitable combination therapies include a combination of a compound of the invention (or a pharmaceutically acceptable salt and/or solvate thereof) with one or more agents selected from agents that are antithrombotics (as outlined above), such as other factor XIIa inhibitors, thrombin receptor antagonists, thrombin inhibitors, factor VIIa inhibitors, factor Xa inhibitors, factor XIa inhibitors, factor IXa inhibitors, adenosine diphosphate anti-platelet agents (e.g., P2Y12 antagonists), fibrinogen receptor antagonists (e.g., to treat or prevent unstable angina or to prevent restenosis and restenosis following angioplasty), and aspirin (aspirin) and platelet aggregation inhibitors.

When combination therapy is employed, the compounds of the invention and the combination agents may be present in the same or different pharmaceutical compositions and may be administered separately, sequentially or simultaneously.

The compounds of the invention may be administered in combination with laser therapy of the retina. Laser therapy in combination with intravitreal injection of VEGF inhibitors is known for the treatment of diabetic macular edema (Elman M, aiello L, beck R et al, "Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema" ophtalmology, 2010, 4, 27).

Intermediate products

Another aspect of the invention provides a compound of formula (II), which is an intermediate in the synthesis of a compound of formula (I):

wherein:

e is selected from CH and N;

g1 is:

g2 is F, cl or Br;

m is 0, 1 or 2;

g3, when present, is independently selected from alkyl, OH, OCF ₃ Aryl group ^b Heteroaryl group ^b Alkoxy, CF ₃ 、CN、-(CH ₂ ) _0-3 -N (G4) (G5), -C (=o) OR12, -C (=o) NR13R14 and halo; with the proviso that when m is 1, G3 is not methyl;

g4 and G5 are independently selected from alkyl groups ^b Aryl group ^b And heteroaryl group ^b Or G4 and G5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered carbon-containing heterocyclic ring, optionally containing another member selected from N, NR, S, SO ₂ And heteroatoms of O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono-or di-substituted with substituents selected from the group consisting of: oxo, alkyl ^b Alkoxy, OH, halo and CF ₃ ；

G6 and G7 are independently selected from methyl, ethyl, n-propyl and isopropyl;

g8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

alkyl group ^b Is of up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); alkyl group ^b Can optionally be independently substituted by 1, 2 or 3A substituent selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

Cycloalkyl having 3 to 6 carbon atoms (C ₃ -C ₆ ) A monocyclic saturated hydrocarbon ring of (2); cycloalkyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl, (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

halo is F, cl, br or I;

Heteroaryl group ^b A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Can optionally be 1, 2 or 3A substituent independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ ；

Heterocycloalkyl is a non-aromatic carbon-containing monocyclic ring containing 5, 6 or 7 ring members, wherein one or two ring members are independently selected from N, NR, S, SO ₂ And O; wherein heterocycloalkyl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, and CN;

r12 is independently selected from H, alkyl or cycloalkyl;

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and salts and/or solvates thereof.

It is understood that "a salt and/or solvate thereof" means "a salt thereof", "a solvate thereof" and "a solvate of a salt thereof".

Preferably, when m is 0; g2 is at any position other than the ring member marked What ring members are substituted

In this case, it is understood that when m is 0; g2 is substituted at any ring member other than the ring member marked

That is, G2 may be substituted at any one of the following ring members where applicable:

but not at the following ring members: />

Preferably, G8 is selected from methyl, n-propyl, isopropyl, n-butyl and isobutyl.

G2 may be selected from Cl and Br. G2 may be Cl. G2 may be Br.

m may be 0 or 1.m may be 1.m may be 0.

G3 is selected from alkyl, alkoxy, OH, OCF ₃ Halo, CN and CF ₃ . Preferably, G3 is halo. When G3 is halo, G3 may be selected from Cl and F. G3 may be Cl. G3 may be F.

E may be CH. E may be N.

Preferably, G1 is selected fromG1 may be->G1 can be/>

Preferably, the compound of formula (II) is selected from Or a salt, solvate or solvate of a salt thereof.

Detailed Description

Definition of the definition

As mentioned above, the term "alkyl" is a radical having up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); the alkyl group may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, -NR13R14, -C (=O) OR13, -C (=O) NR13R14, CN, CF ₃ A halogen group. As mentioned above, "alkyl group ^b "is a radical having up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); alkyl group ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halogen group. Such alkyl or alkyl groups ^b Examples of groups include, but are not limited to, C ₁ -methyl, C ₂ -ethyl, C ₃ -propyl and C ₄ -n-butyl, C ₃ Isopropyl, C ₄ Sec-butyl, C ₄ -isobutyl, C ₄ -tert-butyl and C ₅ Neopentyl, optionally substituted as mentioned above. More specifically, "alkyl" or "alkyl ^b "can be a compound having up to 6 carbon atoms (C ₁ -C ₆ ) Or straight-chain saturated hydrocarbons having 3 to 6 carbon atoms (C ₃ -C ₆ ) Is a branched saturated hydrocarbon of (a) and (b),optionally substituted as mentioned above. More specifically, "alkyl" or "alkyl ^b "can be a compound having up to 4 carbon atoms (C ₁ -C ₄ ) Or straight-chain saturated hydrocarbons having 3 to 4 carbon atoms (C ₃ -C ₄ ) Optionally substituted as mentioned above, which are referred to herein as "small alkyl" or "small alkyl", respectively ^b ". Preferably, "alkyl" or "alkyl ^b "may be defined as" small alkyl "or" small alkyl ^b ”。

As mentioned above, the term "alkylene" is a radical having 1 to 5 carbon atoms ((C) ₁ -C ₅ ) Is a divalent straight-chain saturated hydrocarbon of (2); the alkylene group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl group ^b 、(C ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halogen group. More specifically, "alkylene" may be a compound having 2 to 4 carbon atoms (C ₂ -C ₄ ) More specifically having 2 to 3 carbon atoms (C ₂ -C ₃ ) Optionally substituted as mentioned above.

"aryl" and "aryl ^b "as defined above. Typically, "aryl" or "aryl ^b "will be optionally substituted with 1, 2 or 3 substituents. The substituents optionally present are selected from the substituents described above. Suitable aryl or aryl groups ^b Examples of (a) include phenyl, biphenyl, and naphthyl (each optionally substituted as set forth above). Preferably, "aryl" is selected from phenyl, substituted phenyl (wherein the substituents are selected from the substituents described above) and naphthyl. Most preferably "aryl" is selected from phenyl and substituted phenyl (wherein the substituents are selected from the substituents described above).

As mentioned above, the term "cycloalkyl" is a radical having 3 to 6 carbon atoms (C ₃ -C ₆ ) A monocyclic saturated hydrocarbon of (a); cycloalkyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl, (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halogen group. Examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, optionally substituted as mentioned above. More, theIn particular, "cycloalkyl" may be a monocyclic saturated hydrocarbon having 3 to 5 carbon atoms, more particularly 3 to 4 carbon atoms, optionally substituted as mentioned above.

As mentioned above, the term "alkoxy" is a radical having from 1 to 6 carbon atoms (C ₁ -C ₆ ) O-linked straight-chain hydrocarbons or having 3 to 6 carbon atoms (C ₃ -C ₆ ) O-linked branched hydrocarbons of (2); alkoxy groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: OH, CN, CF ₃ And fluorine. Examples of such alkoxy groups include, but are not limited to, C ₁ -methoxy, C ₂ -ethoxy, C ₃ -n-propoxy and C ₄ N-butoxy (in the case of straight-chain alkoxy groups), and C ₃ -isopropoxy and C ₄ -sec-butoxy and C ₄ Tert-butoxy (in the case of branched alkoxy) optionally substituted as mentioned above. More specifically, "alkoxy" may be a compound having 1 to 4 carbon atoms (C ₁ -C ₄ ) More specifically 1 to 3 carbon atoms (C ₁ -C ₃ ) Straight chain groups of (a). More specifically, "alkoxy" may be a radical having 3 to 4 carbon atoms (C ₃ -C ₄ ) Optionally substituted as mentioned above.

"halo" may be selected from Cl, F, br and I. More specifically, the halo group may be selected from Cl and F.

As mentioned above, a "heteroaryl" is a 5-or 6-membered carbon-containing aromatic ring containing one, two or three ring members selected from N, NR, S and O; heteroaryl groups may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN and CF ₃ . For example, heteroaryl groups may be selected from thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine and pyrazine, optionally substituted as mentioned above.

"heteroaryl group ^a "and" heteroaryl ^b "as defined above. Generally, "heteroaryl ^a "and" heteroaryl ^b "will be optionally substituted with 1, 2 or 3 substituents. Optionally in the presence ofThe substituent of (2) is selected from the above substituents. Suitable heteroaryl groups ^a Or heteroaryl group ^b Examples of groups include thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazole, quinolinyl, isoquinolinyl, 5-azathiaindenyl, indolizinyl, isoindolyl, azaindolyl, indazolyl, benzothiazolyl, An quinolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl and phthalazinyl group (optionally substituted as set out above). Suitable heteroaryl groups ^a Or heteroaryl group ^b Examples of groups include thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, 5-azathiaindenyl, indolizinyl, isoindolyl, indazolyl, benzothiazolyl,>an quinolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl and phthalazinyl group (optionally substituted as set out above). More specifically, "heteroaryl ^a "or" heteroaryl ^b "can be a 9-or 10-membered bicyclic ring as defined and optionally substituted as set forth above. Suitable 9-or 10-membered heteroaryl groups ^a Or heteroaryl group ^b Examples of groups include indolyl, benzimidazolyl, benzotriazole, quinolinyl, isoquinolinyl, 5-azathiaindenyl, indolizinyl, isoindolyl, azaindolyl, indazolyl, benzothiazolyl, and the like>An linyl group, a quinazolinyl group, a quinoxalinyl group, a 1, 8-naphthyridinyl group and a phthalazinyl group. Suitable 9-membered Or a 10 membered heteroaryl ^a Or heteroaryl group ^b Examples of groups include indolyl, benzimidazolyl, benzotriazole, quinolinyl, isoquinolinyl, 5-azathiaindenyl, indolizinyl, isoindolyl, indazolyl, benzothiazolyl,>an linyl group, a quinazolinyl group, a quinoxalinyl group, a 1, 8-naphthyridinyl group and a phthalazinyl group.

Preferably, heteroaryl groups ^b Is heteroaryl group ^c . Heteroaryl group ^c A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ 。

As mentioned above, a "heterocycloalkyl" is a non-aromatic carbon-containing monocyclic ring containing 5, 6 or 7 ring members, wherein one or both ring members are independently selected from N, NR, S, SO ₂ And O; wherein heterocycloalkyl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, and CN. "heterocycloalkyl" may be a non-aromatic carbon-containing monocyclic ring containing 5, 6 or 7 ring members, wherein one or both ring members are independently selected from N, NR and O, optionally substituted as mentioned above. More specifically, "heterocycloalkyl" may be a non-aromatic, carbon-containing monocyclic ring containing 5, 6 or 7 ring members, wherein one or both ring members are independently selected from N or NR8.

As mentioned above, "heterocycloalkyl ^a "is a non-aromatic carbon-containing monocyclic ring containing 3, 4, 5 or 6 ring members, wherein at least one ring member is independently selected from N, NR, S and O; heterocycloalkyl group ^a Optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl, (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halogen group. More specifically, "heterocycloalkyl ^a "can be a non-aromatic carbon-containing monocyclic ring containing 3, 4, 5 or 6 ring members, wherein at least one ring member is independently selected from NR12 and O; heterocycloalkyl group ^a Optionally substituted with 1 or 2 substituents independently selected from the group consisting of: alkyl ((C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halogen group.

The term "O-linked" in terms of such as "O-linked hydrocarbon residues" means that the hydrocarbon residues are bonded to the rest of the molecule via oxygen atoms.

The term "N-linked" in terms of "N-linked pyrrolidinyl" means that the heterocycloalkyl is attached to the remainder of the molecule via a ring nitrogen atom.

In e.g. (CH) ₂ ) _0-6 In the group of-A, "-" represents the point of attachment of the substituent to the remainder of the molecule.

As is apparent from the above definition, and for the avoidance of any doubt, it is to be understood that "Y" is as defined above and does not encompass yttrium.

As is apparent from the above definition, and for the avoidance of any doubt, it is to be understood that "B" is as defined above and does not encompass boron.

As is apparent from the above definition, and for the avoidance of any doubt, it is to be understood that "W" is as defined above and does not encompass tungsten.

As used herein, "salt" (including "pharmaceutically acceptable salts") means physiologically or toxicologically-acceptable salts and includes pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts, as appropriate. For example, (i) where the compounds of the invention contain one or more acid groups, e.g., carboxyl groups, base addition salts (including pharmaceutically acceptable base addition salts) that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines such as diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g., lysine) and the like; (ii) Where the compounds of the invention contain a base, such as an amino group, acid addition salts (including pharmaceutically acceptable acid addition salts) that may be formed include hydrochloride, hydrobromide, sulfate, phosphate, acetate, citrate, lactate, tartrate, methanesulfonate, succinate, oxalate, phosphate, ethanesulfonate, toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, maleate, adipate, fumarate, hippurate, camphorite, hydroxynaphthoate, acetaminobenzoate, dihydroxybenzoate, hydroxynaphthoate, succinate, ascorbate, oleate, bisulfate, trifluoroacetate and the like.

Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: properties, selection and Use" by Stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).

"prodrug" refers to a compound that is convertible in vivo into a compound of the invention by metabolic means (e.g., by hydrolysis, reduction or oxidation). Suitable groups for forming prodrugs are described in 'The Practice of Medicinal Chemistry', 2 nd edition pages 561-585 (2003) and f.j. Leinweber, drug meta.

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term 'solvate' as used herein describes a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g. ethanol). When the solvent is water, the term 'hydrate' is used.

The compounds of the present invention exist in one or more of geometric, optical, enantiomeric, diastereoisomeric and tautomeric forms including, but not limited to, cis and trans forms, E-and Z-forms, R-, S-and meso forms, keto and enol forms. Unless otherwise indicated, reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Such isomers may be separated from their mixtures by application or modification of known methods (e.g., chromatographic techniques and recrystallization techniques), as appropriate. Such isomers may be prepared by applying or modifying known methods (e.g., asymmetric synthesis), as appropriate. For example, where the compounds of the invention are present as a mixture of stereoisomers, one stereoisomer may be present at >90% purity relative to the remaining stereoisomer, or more specifically >95% purity relative to the remaining stereoisomer, or more specifically >99% purity relative to the remaining stereoisomer. For example, where the compounds of the invention are present in enantiomeric form, the compounds may be >90% enantiomeric excess (ee), or more specifically >95% enantiomeric excess (ee), or more specifically >99% ee.

Unless otherwise indicated, compounds of the invention include compounds that differ only in the presence of one or more isotopically enriched atoms. For example where hydrogen is replaced by deuterium or tritium or where carbon is replaced by ¹³ C or ¹⁴ Compounds substituted by C are within the scope of the invention. Such compounds are suitable as analytical tools or probes in, for example, biological assays.

In the context of the present invention, references herein to "treatment" include references to curative, palliative and prophylactic treatment. For example, treatment includes preventing symptoms of disease conditions in which FXIIa is a causative agent.

Method

The compounds of the present invention may be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or any combination thereof). Generally, it will be administered in the form of a formulation in combination with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than a compound of the invention that can impart functional (i.e., drug release rate control) and/or non-functional (i.e., processing aid or diluent) characteristics to a formulation. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

The compounds of the invention intended for pharmaceutical use may be administered in solid or liquid form, such as tablets, capsules or solutions. Pharmaceutical compositions suitable for delivery of the compounds of the present invention and methods of making the same will be apparent to those skilled in the art. Such compositions and methods of making them can be found, for example, in Remington's Pharmaceutical Sciences, 19 th edition (Mack Publishing Company, 1995).

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

For the treatment of conditions such as retinal vascular permeability associated with diabetic retinopathy and diabetic macular edema, the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, particularly suitable for intravitreal injection. It is envisaged that formulations suitable for such use will be in the form of sterile solutions of the compounds of the invention in a suitable aqueous vehicle. The composition may be administered to a patient under the supervision of an attending physician.

The compounds of the invention may also be administered directly into the blood stream, into the subcutaneous tissue, into the muscle or into internal organs. Modes suitable for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Devices suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

Parenteral formulations are typically aqueous or oily solutions. In the case where the solution is an aqueous solution, excipients such as the following may be used: sugars (including but not limited to glucose, mannitol, sorbitol, etc.), salts, carbohydrates, and buffers (preferably to a pH of 3 to 9), but in some applications it may be more desirable to formulate them as a sterile non-aqueous solution or as a dry form to be used in combination with a suitable vehicle, such as sterile pyrogen-free water.

Parenteral formulations may include implants derived from degradable polymers such as polyesters (i.e., polylactic acid lactide, polylactic acid-co-glycolide, polycaprolactone, polyhydroxybutyrate), polyorthoesters, and polyanhydrides. These formulations may be administered via surgical incision into subcutaneous tissue, muscle tissue, or directly into specific organs.

Preparation of parenteral formulations under sterile conditions, such as by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the present invention for use in preparing parenteral solutions may be increased by the use of suitable formulation techniques, such as the incorporation of co-solvents and/or solubility enhancers (such as surfactants, microcellular structures and cyclodextrins).

Preferably, the compounds of the present invention are administered orally. Oral administration may involve swallowing, allowing the compound to enter the gastrointestinal tract, and/or buccal, lingual or sublingual administration, whereby the compound is allowed to pass directly from the mouth into the blood stream.

Formulations suitable for oral administration include solid plugs, solid microparticles, semisolids, and liquids (including multiphase or disperse systems). Exemplary formulations suitable for oral administration include tablets; soft or hard capsules containing multiparticulates or nanoparticles, liquids, emulsions or powders; buccal tablets (including liquid-filled buccal tablets); chewing the tablet; gel; a fast dispersing dosage form; a membrane; oval suppositories; a spray; and buccal/mucoadhesive patches.

Liquid (including multi-phase and dispersion systems) formulations include emulsions, solutions, syrups and elixirs. Such formulations may be presented as fillers in soft or hard capsules (e.g. made from gelatin or hydroxypropyl methylcellulose) and typically comprise a carrier (e.g. water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil), and one or more emulsifying and/or suspending agents. Liquid formulations can also be prepared by reconstitution of a solid (e.g., from a sachet).

The compounds of the invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Liang and Chen Expert Opinion in Therapeutic Patents,2001,11 (6), 981-986.

Formulations of Tablets are discussed in H.Lieberman and L.Lachman at Pharmaceutical Dosage Forms:Tablets, volume 1, (Marcel Dekker, new York, 1980).

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.1mg to 10,000mg, or between 1mg and 5000mg, or between 10mg and 1000mg, depending of course on the mode of administration.

The total dose may be administered in a single dose or in divided doses and may be outside the typical ranges given herein at the discretion of the physician. These doses are based on an average human subject weighing about 60kg to 70 kg. The physician will be able to readily determine the dosage of subjects having weights outside this range, such as infants and elderly persons.

Numbering plan

The invention is also described by the following numbered embodiments:

1. a compound of the formula (I),

wherein:

z is 2-pyridone or 4-pyridone,

X is selected from SO ₂ And CR1R2;

R2 is selected from H and small alkyl; or (b)

y is selected from NR12, O and CR3R4;

r3 and R4 are independently selected from H and alkyl; or (b)

b is selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group;

(iii) ComprisesA 5-to 6-membered non-aromatic heterocycle of one N-ring member, which may be saturated or unsaturated with 1 or 2 double bonds where applicable, wherein the non-aromatic heterocycle is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, aryl ^b 、OH、OCF ₃ Halo, oxo, CN and CF ₃ The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

n is 0, 1 or 2;

AW-is selected from:

A is a 4-to 15-membered monocyclic, bicyclic or tricyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is optionally substituted with 1, 2, 3 or 4 substituents independently selected from:halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

halo is F, cl, br or I;

r12 is independently selected from H, alkyl or cycloalkyl;

r13 and R14 are independently selected from H, alkyl ^b Aryl group ^b And heteroaryl group ^b Or R13 and R14 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered carbon-containing heterocycle, any of whichOptionally contains another component selected from N, NR, S, SO ₂ And heteroatoms of O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono-or di-substituted with substituents selected from the group consisting of: oxo, alkyl ^b Alkoxy, OH, halo and CF ₃ ；

And tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof.

2. A compound of formula (I) according to numbered embodiment 1, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein when AW-is-C (=O) NR12- (CH) ₂ ) _0-6 -A or- (CH) ₂ ) _0-6 -C(＝O)-(CH ₂ ) _0-6 at-A, AW-is bonded at a carbocycle member of Z.

3. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is a 6-or 5-membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O; or phenyl.

4. A compound of formula (I) according to numbered embodiment 3, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is a 6-or 5-membered heteroaromatic ring containing 1 or 2 ring members independently selected from N and S; or phenyl.

5. The compound of formula (I) according to any one of numbered embodiments 1 to 2, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is a 6 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N; or phenyl; or (b)

Z is 2-pyridone or 4-pyridone.

6. The compound of formula (I) according to any one of numbered embodiments 1 to 3 or 5, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salts and/or solvates thereof,

wherein Z is a 6 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N.

7. The compound of formula (I) according to any one of numbered embodiments 1 to 3, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole.

8. A compound of formula (I) according to numbered embodiment 7, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is selected from pyrazole, phenyl, pyrimidine, pyridine and thiazole.

9. A compound of formula (I) according to numbered embodiment 8, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is selected from phenyl, pyrimidine and pyridine.

10. The compound of formula (I) according to any one of numbered embodiments 1 to 4 or 7 to 9, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is phenyl.

11. The compound of formula (I) according to any one of numbered embodiments 1 to 3, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein Z is a 5 membered heteroaromatic ring containing 1, 2 or 3 ring members independently selected from N, S and O.

12. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein the compound is selected from:

/>

13. a compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein X is CR1R2.

14. A compound of formula (I) according to numbered embodiment 13, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein X is CH ₂ 。

15. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Y is NR12.

16. A compound of formula (I) according to numbered embodiment 15, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein Y is NH.

17. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

(i) Heteroaryl group ^a ；

(iii) A fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring comprising an aromatic ring fused to a non-aromatic ring, wherein the bicyclic ring optionally comprises one or two N ring members, wherein the fused 5, 5-bicyclic, 6, 5-bicyclic, or 6, 6-bicyclic ring may be optionally substituted with 1, 2, or 3 substituents, up to three substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ A halogen group,Oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via the 6-membered or 5-membered ring.

18. The compound of formula (I) according to any one of numbered embodiments 1 to 16, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group; and

19. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

20. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is heteroaryl ^a 。

21. The compound of formula (I) according to numbered embodiment 20, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Y is heteroaryl ^a The carbon atom on the ring is attached to B.

22. A compound of formula (I) according to numbered embodiment 21, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein Y is heteroaryl ^a At a carbon atom on the ring, to B, and two are adjacent to the heteroaryl group ^a The ring atoms of the carbon atoms to which Y is attached are carbon.

23. The compound of formula (I) according to any one of numbered embodiments 20 to 22, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

isoquinolinyl radicalOptionally as heteroaryl ^a Is substituted;

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridine compoundBase groupOptionally as heteroaryl ^a Is substituted.

24. A compound of formula (I) according to numbered embodiment 23, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

isoquinolinyl selected fromOptionally as heteroaryl ^a Is substituted;

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

25. The compound of formula (I) according to any one of numbered embodiments 20 to 23, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein B is selected from:

isoquinolinyl radicalBy NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents; />

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

26. A compound of formula (I) according to numbered embodiment 25, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

isoquinolinyl selected fromBy NH ₂ Substituted, optionally as heteroaryl ^a Further substituted with 1 or 2 substituents;

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

27. The compound of formula (I) according to any one of numbered embodiments 20 to 23 or 25, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salts and/or solvates thereof,

Wherein B is selected from:

is NH at position 1 ₂ Substituted isoquinolinylOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents; />

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

28. A compound of formula (I) according to numbered embodiment 27, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents;

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

29. A compound of formula (I) according to numbered embodiment 28, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein B is:

is NH at position 1 ₂ Substituted isoquinolinyl selected fromOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents.

30. A compound of formula (I) according to numbered embodiment 29, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is:

is NH at position 1 ₂ Substituted isoquinolinylOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents.

31. A compound of formula (I) according to numbered embodiment 29, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is:

32. A compound of formula (I) according to numbered embodiment 28, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein B is:

6-azaindolylOptionally as heteroaryl ^a Is substituted.

33. A compound of formula (I) according to numbered embodiment 28, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is:

7-azaindolylOptionally as heteroaryl ^a Is substituted.

34. A compound of formula (I) according to numbered embodiment 28, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is:

pyridine compoundBase groupOptionally as heteroaryl ^a Is substituted.

35. The compound of formula (I) according to any one of numbered embodiments 20 to 22, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is isoquinolinyl, optionally as heteroaryl ^a Is substituted.

36. A compound of formula (I) according to numbered embodiment 35, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is isoquinolinyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

37. A compound of formula (I) according to numbered embodiment 36, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is isoquinolinyl, substituted with 1, 2 or 3 substituents independently selected from alkoxy.

38. A compound of formula (I) according to numbered embodiment 37, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein B is isoquinolinyl, substituted with 1, 2 or 3 substituents selected from-OMe.

39. A compound of formula (I) according to numbered embodiment 38, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is isoquinolinyl, substituted with NH ₂ Substituted and optionally e.g. heteroaryl ^a Substituted with 1 or 2 other substituents.

40. The compound of formula (I) according to any one of numbered embodiments 20 to 22, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is a 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2, 3 or 4 ring members independently selected from N, NR, S and O, where applicable; which may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

41. The compound of formula (I) according to any one of numbered embodiments 20 to 40, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein the substituents optionally present on B are independently selected, where applicable, from: alkyl, alkoxy, OH, OCF ₃ Halo, aryl ^b 、-(CH ₂ ) _0-3 -NR13R14, heteroaryl ^b -C (=o) OR12, -C (=o) NR13R14 and CF ₃ 。

42. The compound of formula (I) according to any one of numbered embodiments 20 to 41, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

43. a compound of formula (I) according to numbered embodiment 42, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein B is selected from:

44. The compound of formula (I) according to any one of numbered embodiments 20 to 28, 32 to 33, or 40 to 42, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein when B is heteroaryl ^a And is a 9 membered bicyclic aromatic ring containing a 5 membered ring fused to a 6 membered ring, and when B is connected to Y via a 6 membered ring, the 9 membered bicyclic aromatic ring contains 1 or 2 ring members independently selected from N, NR, S and O; and e.g. heteroaryl ^a Optionally substituted.

45. The compound of formula (I) according to any one of numbered embodiments 20 to 28, 32 to 33, or 40 to 42, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein when B is heteroaryl ^a And is selected from 6-azaindolylAnd 7-azaindolyl +.>When B is heteroaryl ^a Optionally substituted, and any optionally present substituents are located, where applicable, at any ring member other than the ring member labeled # or members.

46. The compound of formula (I) according to any one of numbered embodiments 1 to 45, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein n is 0 or 1.

47. The compound of formula (I) according to any one of numbered embodiments 1 to 45, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein n is 1 or 2.

48. A compound of formula (I) according to numbered embodiment 46, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein n is 0.

49. The compound of formula (I) according to any one of numbered embodiments 46 or 47, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein n is 1.

50. The compound of formula (I) according to any one of numbered embodiments 1 to 49, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein R5 is independently selected from CH ₃ 、OH、CH ₂ OH、OCH ₃ 、OiPr、CF ₃ 、F、Cl、(CH ₂ ) _0-6 COOH、CN、CH ₂ F、CHF ₂ 、CH ₂ OCH ₃ And

51. a compound of formula (I) according to numbered embodiment 50, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein R5 is independently selected from F, CH ₂ OH and

52. a compound of formula (I) according to numbered embodiment 51, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

wherein R5 is F.

53. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein AW is selected from the group consisting of-A, -OCH ₂ -A、-CH ₂ O-A、-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C(＝O)-A。

54. A compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein a is a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

Wherein when a is a bicyclic ring system, the bicyclic ring system is fused, bridged or spiro-linked.

55. The compound of formula (I) according to numbered embodiment 54, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

Wherein a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N and O, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

56. A compound of formula (I) according to numbered embodiment 55, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein a is a 4-to 12-membered mono-or bi-cyclic ring system containing one N-ring member and optionally one or two other N-ring members, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from the following, where applicable: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

57. The compound of formula (I) according to numbered embodiment 54, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein A is selected from:

58. a compound of formula (I) according to numbered embodiment 57, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof,

wherein A is selected from:

59. a compound of formula (I) according to numbered embodiment 56, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof,

wherein A is selected from:

60. a compound of formula (I) according to numbered embodiment 59, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof,

Wherein A is selected from:

61. a compound of formula (I) according to numbered embodiment 59, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes, and pharmaceutically acceptable salts and/or solvates thereof,

wherein A is selected from:

62. a compound of formula (I) according to numbered embodiment 61, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein A is selected from:

63. a compound of formula (I) according to any preceding numbered embodiment, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof,

wherein heteroaryl is ^b Is heteroaryl group ^c The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

Heteroaryl group ^c A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1 or 2 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ 。

64. A compound selected from tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

65. A compound selected from tables 1a, 2a, 3, 4a, 5a, 6, 7 and 8a, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

66. A pharmaceutical composition comprising: the compound according to any one of numbered embodiments 1 to 65, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable excipient.

67. A compound as defined in any one of numbered embodiments 1 to 65 or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to numbered embodiment 66, for use in medicine.

68. Use of a compound as defined in any one of numbered embodiments 1 to 65 or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to numbered embodiment 66, for the manufacture of a medicament for the treatment or prophylaxis of a disease or condition associated with factor XIIa activity.

69. A method of treating a disease or condition associated with factor XIIa activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of numbered embodiments 1 to 65, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to numbered embodiment 66.

70. A compound as defined in any one of numbered embodiments 1 to 65 or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to numbered embodiment 66, for use in a method of treatment of a disease or condition associated with factor xlla activity.

71. The use as described in numbered embodiment 68, the method as described in numbered embodiment 69 or the compound, pharmaceutically acceptable salt and/or solvate thereof or pharmaceutical composition for use as described in numbered embodiment 70, wherein the disease or condition associated with factor XIIa activity is bradykinin mediated vascular edema.

72. The use according to numbered embodiment 71, the method according to numbered embodiment 71 or the compound used according to numbered embodiment 71, a pharmaceutically acceptable salt and/or solvate thereof or a pharmaceutical composition thereof, wherein bradykinin mediated vascular edema is hereditary vascular edema.

73. The use of numbered embodiment 71, the method of numbered embodiment 71, or the compound used as described in numbered embodiment 71, pharmaceutically acceptable salt and/or solvate thereof, or pharmaceutical composition thereof, wherein bradykinin-mediated angioedema is non-hereditary.

74. The use as described in numbered embodiment 68, the method as described in numbered embodiment 69 or the compound, pharmaceutically acceptable salt and/or solvate thereof or pharmaceutical composition for use as described in numbered embodiment 70, wherein the disease or condition associated with factor XIIa activity is selected from vascular hyperpermeability; stroke (including ischemic stroke and hemorrhagic accidents); retinal edema; diabetic retinopathy; DME; retinal vein occlusion; and AMD.

75. The use as described in numbered embodiment 68, the method as described in numbered embodiment 69 or the compound, pharmaceutically acceptable salt and/or solvate thereof or pharmaceutical composition for use as described in numbered embodiment 70, wherein the disease or condition associated with factor XIIa activity is a thrombotic disorder.

76. The use of numbered embodiment 75, the method of numbered embodiment 75, or the compound used as described in numbered embodiment 75, a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition thereof, wherein the thrombotic disorder is thrombosis; thromboembolism caused by the increased tendency of the medical device to coagulate blood by contact with blood; pre-thrombotic conditions such as Disseminated Intravascular Coagulation (DIC), venous Thromboembolism (VTE), cancer-associated thrombosis, complications arising from mechanical and biological heart valves, complications arising from catheters, complications arising from ECMO, complications arising from LVAD, complications arising from dialysis, complications arising from CPB, sickle cell disease, arthroplasty, tPA-induced thrombosis, peck-sch's syndrome, and bujia syndrome; atherosclerosis; covd-19; acute Respiratory Distress Syndrome (ARDS); idiopathic Pulmonary Fibrosis (IPF); rheumatoid Arthritis (RA); and cold-induced urticaria-type autoinflammatory syndrome.

77. The use as described in numbered embodiment 68, the method as described in numbered embodiment 69 or the compound, pharmaceutically acceptable salt and/or solvate thereof or pharmaceutical composition for use as described in numbered embodiment 70, wherein the disease or condition associated with factor XIIa activity is selected from neuroinflammation; neuroinflammatory/neurodegenerative disorders such as MS (multiple sclerosis); other neurodegenerative diseases such as Alzheimer's disease, epilepsy and migraine; sepsis; bacterial sepsis; inflammation; vascular high permeability; and allergies.

78. The use of any one of numbered embodiments 68 or 71 to 77, the method of any one of numbered embodiments 69 or 71 to 77, or the compound used of any one of numbered embodiments 70 or 71 to 77, pharmaceutically acceptable salt and/or solvate thereof, or pharmaceutical composition thereof, wherein the compound targets FXIIa.

79. A compound of the formula (II),

wherein:

e is selected from CH and N;

g1 is:

g2 is F, cl or Br;

m is 0, 1 or 2;

g8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

alkyl is a radical having up to 10 carbon atoms (C ₁ -C ₁₀ ) Straight-chain saturated hydrocarbons of (3) or having 3 to10 carbon atoms (C) ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); the alkyl group may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, -NR13R14, -C (=O) OR13, -C (=O) NR13R14, CN, CF ₃ A halo group;

halo is F, cl, br or I;

r12 is independently selected from H, alkyl or cycloalkyl;

80. The compound of formula (II) according to numbered embodiment 79, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein when m is 0; g2 is substituted at any ring member other than the ring member marked

81. The compound of formula (II) according to any one of numbered embodiments 79 or 80, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

Wherein G8 is selected from the group consisting of methyl, n-propyl, isopropyl, n-butyl and isobutyl.

82. The compound of formula (II) according to any one of numbered embodiments 79 to 81, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein G2 is selected from Cl and Br.

83. A compound of formula (II) according to numbered embodiment 82, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G2 is Cl.

84. A compound of formula (II) according to numbered embodiment 82, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G2 is Br.

85. The compound of formula (II) according to any one of numbered embodiments 79 to 84, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

Wherein m is 0 or 1.

86. The compound of formula (II) according to any one of numbered embodiments 79 to 85, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein m is 1.

87. The compound of formula (II) according to any one of numbered embodiments 79 to 86, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein G3 is selected from alkyl, alkoxy, OH, OCF ₃ Halo, CN and CF ₃ 。

88. The compound of formula (II) according to numbered embodiment 87, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G3 is halo.

89. The compound of formula (II) according to numbered embodiment 88, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

Wherein G3 is selected from Cl and F.

90. The compound of formula (II) according to numbered embodiment 89, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G3 is Cl.

91. The compound of formula (II) according to numbered embodiment 89, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G3 is F.

92. The compound of formula (II) according to any one of numbered embodiments 79 to 85, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein m is 0.

93. The compound of formula (II) according to any one of numbered embodiments 79 to 92, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

Wherein E is CH.

94. The compound of formula (II) according to any one of numbered embodiments 79 to 92, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein E is N.

95. The compound of formula (II) according to any one of numbered embodiments 79 to 94, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers, and racemic and non-racemic mixtures thereof), deuterated isotope and salt and/or solvate thereof,

wherein G1 is selected from

96. A compound of formula (II) according to numbered embodiment 95, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

wherein G1 is

97. A compound of formula (II) according to numbered embodiment 95, or tautomers, isomers, stereoisomers (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotopes and salts and/or solvates thereof,

Wherein G1 is/>

98. A compound selected from

Or a salt, solvate or solvate of a salt thereof.

Synthesis method

The compounds of the present invention may be prepared according to the following schemes and procedures of the examples using appropriate materials and are further exemplified by the specific examples provided below. Furthermore, by utilizing the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that are within the scope of the invention as claimed herein. However, the compounds illustrated in the examples should not be construed as forming the only species considered as the invention. Those skilled in the art will readily appreciate that known variations of the conditions, processes, and order of performing the synthetic steps in the following preparation procedures may be used to prepare these compounds.

The compounds and intermediates of the invention may be isolated in the form of pharmaceutically acceptable salts thereof, such as those previously described above. The interconversion between the free form and the salt form will be readily apparent to those skilled in the art.

It may be necessary to protect the reactive functional groups (e.g., hydroxyl, amino, thio or carboxyl) in the intermediates used in the preparation of the compounds of the invention to avoid undue participation in the reactions that lead to the formation of the compounds. Conventional protecting groups may be used, such as those described in t.w. greene and p.g. m.wuts, under "Protective groups in organic chemistry" John Wiley and Sons, 4 th edition, 2006. For example, a common amino protecting group suitable for use herein is t-butoxycarbonyl (boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid in an organic solvent such as dichloromethane. Alternatively, the amino protecting group may be a benzyloxycarbonyl (Cbz or Z) which may be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere; or 9-fluorenylmethoxycarbonyl (Fmoc), which may be removed from a solution of a secondary organic amine, such as diethylamine or piperidine, in an organic solvent. The carboxyl groups are usually protected in the form of esters, such as methyl, ethyl, benzyl or tert-butyl esters, which can all be removed by hydrolysis in the presence of a base, such as lithium hydroxide or sodium hydroxide. Benzyl protecting groups can also be removed by hydrogenation in the presence of a palladium catalyst under a hydrogen atmosphere, while tert-butyl groups can also be removed by trifluoroacetic acid. Alternatively, the trichloroethyl protecting group is removed with zinc in acetic acid. A common hydroxy protecting group suitable for use herein is methyl ether, the deprotection conditions comprise refluxing in 48% aqueous HBr, or by stirring with borane tribromide in an organic solvent such as DCM. Alternatively, where the hydroxyl group is protected as anisole, the deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen atmosphere.

Graphic representations of racemic, bisnon-racemic (ambiscalamic) and non-racemic or enantiomerically pure compounds as used herein were obtained from Maehr j. Chem. Ed.62,114-120 (1985): solid wedge shapeAnd intermittent wedge->For representing the absolute configuration of chiral elements; wave line->Indicating that the denial may result in any stereochemical implication of the bond that it represents; solid thick line->And discontinuous thick line->Geometric descriptors indicating the relative configuration shown but indicating the racemic nature; and wedge profile +.>And dotted line->An enantiomerically pure compound of indefinite absolute configuration. For the corresponding wedge profile here +>And dotted line->We define R and S as single enantiomers indicating an undefined absolute configuration.

Thus, for example, in examples 4267 and 4412 below, the synthesis of 6-N- ({ 2- [ (7S) -5h,6h,7h,8 h-imidazo [1,2-a ] pyridin-7-ylmethoxy ] pyridin-4-yl } methyl) isoquinoline-1, 6-diamine and 6-N- ({ 2- [ (7R) -5h,6h,7h,8 h-imidazo [1,2-a ] pyridin-7-ylmethoxy ] pyridin-4-yl } methyl) isoquinoline-1, 6-diamine is described. The (R) and (S) are intended to indicate that the product is a single enantiomer having the described properties (eq.nmr, HPLC, residence time, etc.), wherein each chiral center is considered to be the configuration shown based on indirect evidence, but the absolute configuration has not been confirmed. Thus, for compound 4267, description:

Meaning that the compound is a single one of the following two stereoisomers, and likely the first:

as used herein, includes descriptions of wedges or dashed lines (e.g ) Indicating that the purity of the relative or absolute configuration covered by the structure is at least 80% ee, preferably>90％ee。

As used herein, when a compound has an asymmetric center, it contains a description of a simple line (e.g) The indicated structures include any and all stereoisomers, regardless of enantiomeric purity.

The invention is illustrated by the following non-limiting examples, in which the following abbreviations and definitions are used:

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unless otherwise specified, all reactions were carried out under a nitrogen atmosphere.

Hydrogenation is generally carried out using H-The reactor (manufactured by Thales nano, inc., hungary).

References to the use of microwaves, microwave reactors, microwave heating and microwave irradiation all refer to the use of CEM Discover microwave reactors.

References to the use of a phase separator refer to a column containing selectively permeable, optimized frit material that separates the aqueous phase from the organic phase under gravity.

¹ H NMR spectra were recorded on a Bruker (500 MHz or 400 MHz) spectrometer and reported as chemical shifts (ppm).

Molecular ions were obtained using LCMS using appropriate conditions selected from the group consisting of:

-Chromolith Speedrod RP-18e column, 50×4.6mm, linear gradient 10% to 90%0.1% HCO ₂ H/MeCN at 0.1% HCO ₂ H/H ₂ O, flow rate 1.5mL/min for 13 min;

agilent, X-Select, acidic, 5-95% MeCN/water for 4min. Data were collected using a Thermofinnigan Surveyor MSQ mass spectrometer with electrospray ionization in combination with a Thermofinnigan Surveyor LC system;

LCMS (Waters Acquity UPLC, C18, waters X-Bridge UPLC C18,1.7 μm, 2.1X30 mm, alkaline (0.1% ammonium bicarbonate) 3min method;

LCMS (Agilent, X-Select, waters X-Select C18,2.5 μm, 4.6X10 mm, acidic 4min method, 95-5 MeCN/water);

LCMS (Agilent, alkaline, waters X-Bridge C18,2.5 μm, 4.6X10 mm, alkaline 4min method, 5-95 MeCN/water;

acquity UPLC BEH C18A 1.7. Mu.M column, 50X 2.1mm, linear gradient 10% to 90%0.1% HCO2H/MeCN in 0.1% HCO2H/H2O for 3min, flow rate 1mL/min. Data was collected using a Waters Acquity UPLC mass spectrometer with a quadrupoles daltons (quadrupoles), photodiode array and electrospray ionization detector.

Flash chromatography is typically performed on 'silica' (chromatography silica gel, 0.035 to 0.070mm (220 to 440 mesh) (e.g., merck silica gel 60)) and nitrogen pressure up to 10 p.s.i. is applied to accelerate column elution. Alternatively, a pre-prepared silica gel cartridge is used.

The term "preparative HPLC" refers to reverse phase preparative HPLC purification.

Lyophilization (or freeze drying) procedures are generally well known in the art. Typically, minimal MeCN is added to aid dissolution to dissolve the material in water, if necessary, and is typically frozen by rapid cooling in a cold bath at-78 ℃. The resulting frozen solid mixture was evaporated to dryness in vacuo.

The term "concentrating" refers to evaporating the solvent under reduced pressure using a rotary evaporator with heating as necessary.

All solvents and commercial reagents were used as received.

IUPAC chemical names were generated using automated software such as lexischem from OpenEye Scientific Software, inc, which is provided in the form of Dotmatics Studies Notebook components. Other automation software for naming includes ChemDraw (PerkinElmer) or Chemaxon software provided as a component of marvinsktech or a component of IDBS E-WorkBook.

The example compounds described herein can be prepared using conventional synthetic methods such as, but not limited to, the pathways outlined in the following general schemes using, for example, the following general methods.

General method

1. General procedure 1 (GM 1): s is S _N Ar alkylation (O and N)

a. General procedure 1a (GM 1 a): s using NaH _N Ar O-alkylation

To a suspension of NaH (60% wt on mineral oil) (1.04 eq) in DMF was added dropwise a solution of alcohol (1.02 eq) in DMF over 2min in an ice/water bath. The mixture is allowed to warm up to rt,hold for 5min before cooling again in an ice/water bath and treatment with pyridinyl halide (1.0 eq). The reaction mixture was maintained in an ice/water bath for 1h, then warmed to rt and held for 18h. The reaction mixture was cooled in an ice/water bath and saturated Na was added ₂ CO ₃ (aqueous solution) followed by the addition of water. It was extracted with EtOAc (×3) and the organic phases were combined, washed with 1:1 water/brine and brine. The organic phase was dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography.

b. General procedure 1b (GM 1 b): using Cs ₂ CO ₃ S of (2) _N Ar O-alkylation

Cs was added to a solution of alcohol (1.0 eq) and pyridinyl halide (1.0 eq) in MeCN ₂ CO ₃ (2.0 eq) and the mixture was stirred in a sealed vial at 50℃for 18-72h. The product was isolated and purified using one of the following methods:

i) The reaction mixture was cooled to rt and diluted with water (10 mL). The crude product was extracted into DCM and dried (MgSO ₄ ) Filtering and concentrating. Purification of the residue by flash chromatography

ii) passing the reaction mixture throughFiltration and concentration of the filtrate gives the crude product, which is used without further purification or purified by flash chromatography

iii) The crude reaction mixture was passed directly through SCX in MeOH. Wash SCX with MeOH and with 7M NH ₃ The product was eluted with MeOH. The crude product was purified by flash chromatography.

c. General procedure 1c (GM 1 c): s using NaOtBu _N Ar O-alkylation

A solution of alcohol (1.0 eq), aryl bromide (1.0 eq) and NaOtBu (3.0 eq) in NMP was stirred in the microwave at 140℃for 4h. The crude reaction mixture was loaded onto SCX in MeOH and washed with MeOH, and with 7M NH-containing ₃ The product was eluted with MeOH (50 mL). The product was concentrated and purified by flash chromatography or preparative HPLC.

d. General procedure 1d (GM 1 d): s is S _N Ar N-alkylation

Amine (1.0 eq) (106 mg,0.82 mmol) and halopyridine (1.0 eq) (100 mg,0.82 mmol) were dissolved in MeCN (3 mL). Adding K ₂ CO ₃ (3.0 eq) (340 mg,2.46 mmol) and the reaction stirred under heat or microwave radiation at 60-120℃for 60-90min. The reaction was diluted with water and with isopropanol/CHCl ₃ (1:10) (. Times.3) extraction. The combined organics were washed with brine and dried (MgSO ₄ ) And concentrated. The product was isolated and used directly or purified by flash chromatography.

2. General procedure 2 (GM 2): cyanation

Aryl bromide (1.0 eq) and Zn (CN) ₂ (1.5 eq) was suspended in NMP. The mixture was degassed with nitrogen for 10min before Pd (PPh ₃ ) ₄ (0.15 eq) and the mixture was further degassed via 3 vacuum nitrogen cycles. In N ₂ The reaction was then heated to 80℃and held for 16-90h. The reaction was diluted with EtOAc. Saturated NaHCO for the organic phase ₃ (aqueous solution) (. Times.2) and brine (. Times.3), washed, dried (Na) ₂ SO ₄ ) Filtering and concentrating. The product was purified by flash chromatography.

3. General procedure 3 (GM 3): reduction of

a. General procedure 3a (GM 3 a): reducing nitrile; h-containing cartridges of Pd/C or Raney Ni

Dissolving nitrile through H-0.5MNH of reactor (Pd/C or Raney Nickel cartridge) ₃ In MeOH solution, typical conditions are: 50 ℃, 'full' hydrogen delivery mode (50 bar), flow rate: 1mL/min. The reaction was concentrated to give the product, which was used without further purification.

b. General procedure 3b (GM 3 b): nitrile, amide and ester reduction; containing LiAlH ₄ THF of (2)

To a solution of amide, nitrile or ester (1.0 eq) in THF in ice/water bath was added LiAlH dropwise ₄ (2M in THF) (2.0 eq) and heating the reaction mixtureTo rt, followed by stirring for 4-18h. The reaction mixture was cooled in an ice/water bath with Na ₂ SO ₄ .10H ₂ O (3.5 eq) was batched and stirred for 30min before drying (MgSO ₄ ) Filtered and washed with THF (10 mL). The filtrate was concentrated to give the crude product which was used without purification or purified by flash chromatography.

c. General procedure 3c: borane-THF

A solution of nitrile (1.0 eq) in THF was cooled in an ice/water bath, after which borane (1M in THF, 2.0 eq) was added dropwise. The reaction was warmed to rt and then heated to 60 ℃ for 16-96h. MeOH was added and heating was continued at 60 ℃ for 24h before cooling to rt and concentrating. The product was isolated and purified using one of the following methods:

i) The crude product was loaded onto SCX in MeOH and washed with MeOH. By using a catalyst containing 7M NH ₃ The product was eluted with MeOH and the eluate was concentrated.

ii) purification of the crude product by flash chromatography

iii) Boc is to be Boc ₂ O (1.2 eq) was added to the crude reaction mixture and stirred overnight. The solvent was evaporated in vacuo. The product was dissolved in DCM, washed with water and brine, dried (Na ₂ SO ₄ ) Filtering and concentrating. The boc-protected amine is purified without further purification or by flash chromatography

d. General procedure 3d: niCl ₂

Nitrile (1.0 eq), niCl were cooled in an ice/water bath ₂ .6H ₂ O (1.0 eq) and Boc ₂ A solution of O (3.0 eq) in MeOH was added in portions with NaBH ₄ (5.0 eq). The reaction was warmed to rt and stirred for 18h. Water was added and the reaction mixture was filtered, washed with THF and concentrated. The crude product was purified by flash chromatography.

e. General method 3e: hydrogenation; pd/C

To a solution of nitrile (1.0 eq) in MeOH or EtOH was added 10% Pd/C (0.1-0.2 eq) under an inert atmosphere. Optionally adding a catalyst such as HCl, sulfuric acid or Boc ₂ Additive of O. At H ₂ (g) The reaction was stirred under an atmosphere for 2-72h. Through warpFiltering to remove catalyst, and adding herba Vernoniae Cicadae>Washed with EtOH. The product was isolated after concentration of the filtrate and used directly or purified by flash chromatography.

f. General method 3f: ring saturation reduction

The biaryl ring (1.0 eq) was dissolved in EtOH and reacted in H-The hydrogenation was carried out at 70℃and 50 bar at 1mL/min using 10% Pd/C CatCart, and recycled as necessary. The solvent was removed in vacuo to give the product, which was used without purification.

4. General procedure 4 (GM 4): buchwald (Buchwald)

By N ₂ (g) Purging benzylamine or heteroarylamine (1.0 eq), aryl halide (1.1 eq) and such as Cs ₂ CO ₃ Or a suspension of NaOtBu base (2.0 eq) in a degassed solvent such as THF or 1, 4-dioxane. BrettPhos Pd G3 (0.11 eq) was added (or otherwise Ruphos Pd G3 was added where indicated), and the mixture was degassed and N was used ₂ (g) Purging for 5min. The reaction was heated in a sealed vial at rt to 80 ℃ for 30min to 3 days, as required. The product was isolated and purified using one of the following methods:

i) The reaction was quenched with AcOH (2.0 eq) and concentrated. The crude material is treated by SCX and NH-containing ₃ Is eluted and purified followed by flash chromatography or preparative HPLC.

ii) quenching the reaction with AcOH (2.0 eq) viaFiltered, washed with EtOAc, and the filtrate concentrated. Purification of the crude product by flash chromatography

iii) The reaction mixture was acidified with AcOH (2.0 eq) and stirred for 5min, 1MNH was added ₃ Is added, and the reaction mixture is concentrated on silica gel and purified by flash chromatography.

iv) dry-loading the reaction mixture onto silica gel and purification by flash chromatography.

5. General procedure 5 (GM 5): s is S _N 2 alkylation (O and N)

a. General procedure 5a: s is S _N 2 alkylation: naH (NaH)

To a suspension of NaH (60% wt on mineral oil) (1.1 eq) in DMF was added dropwise a solution of alcohol (1.0 eq) in DMF over 2min in an ice/water bath. The mixture was warmed to rt, held for 5min, then cooled again in an ice/water bath and treated with a solution of alkyl halide (1.0 eq) in DMF for 2min. The mixture was maintained in an ice/water bath for 1h, after which it was warmed to rt and stirred for 2-18h. Adding saturated NH ₄ Cl (aqueous) (50 mL) or saturated NaHCO ₃ (aqueous) and extracted with EtOAc (×3). The organic phases were combined and dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography.

b. General procedure 5b: s is S _N 2 alkylation; cs (cells) ₂ CO ₃ Or K ₂ CO ₃

Alkyl halides (1-2 eq) (1.20 g,4.30 mmol), pyrazoles (1.0 eq) and e.g. K are stirred in a microwave at 130 ℃ ₂ CO ₃ Or Cs ₂ CO ₃ 2h in a solvent such as NMP. The reaction was quenched with MeOH (5 mL) and diluted with water (50 mL). The product was extracted into TBME (2X 50 mL) and washed with brine (50 mL). The organic layer was dried (Na ₂ SO ₄ ) Filtering and concentrating. The product was used as such, or purified by flash chromatography

6. General procedure 6: (GM 6): chlorination

a. General procedure 6a (GM 6 a): chlorination via methanesulfonate

Methanesulfonyl chloride (2.5 eq) (0.6 mL,8.32 mmol) was added to a solution of TEA (2.8 eq) and alcohol (1.0 eq) in DCM (20 mL) while cooling in an ice/water bath. The reaction was stirred at rt for 18h. The reaction was diluted with DCM and saturated NaHCO ₃ (aqueous solution) washing. The aqueous layer was extracted with DCM (3×25 mL) and the combined organics were washed with brine, dried (Na ₂ SO ₄ ) Filtering and concentrating. Purification of the crude product by flash chromatography。

b. General procedure 6b (GM 6 b): chlorination via NCS

A solution of indole or azaindole (1.0 eq) in dichloroethane was protected from light and treated with NCS (3.75 eq) at rt for 12-48h. The mixture was treated with 1M HCl (aqueous solution) and the phases were separated. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) Filtering, concentrating and purifying by flash chromatography.

7. General procedure 7 (GM 7): boc deprotection; HCl or TFA

a. General procedure 7a: boc deprotection; HCl/dioxane

A suspension of boc-protected amine (1.0 eq) treated with 4M HCl in 1, 4-dioxane was added and the reaction stirred at rt for 2-24h. The product was isolated and purified using one of the following methods:

I. concentrating the reaction mixture, optionally with Et ₂ O or toluene azeotropes to give the product as the hydrochloride salt.

The reaction mixture was concentrated and the product was converted to free base using a bicarbonate cartridge loaded in MeOH. The filtrate was concentrated and treated with Et ₂ O is ground to obtain the product.

b. General procedure 7b: boc deprotection; TFA (TFA)

The mixture of boc-protected amine (1.0 eq) in DCM was treated with TFA (10.0 eq) and stirred at rt for 2h. The mixture was passed directly through SCX and washed with MeOH. The product was treated with 7M NH ₃ The solution in MeOH was eluted and concentrated. The crude product was purified by flash chromatography or preparative HPLC.

8. General procedure 8 (GM 8): amide coupling

To a solution of formic acid (1.03 mmol) in DCM (10 mL) in an ice/water bath was added HOBt (1.1 eq), EDC (1.3 eq) and TEA (5.0 eq). After 10min, amine (1.0 eq) was added and the mixture was stirred at rt for 15h. The reaction was diluted with DCM and saturated NaHCO ₃ Aqueous (10 mL), water and brine. The organic layer was dried (MgSO ₄ ) Filtering and concentrating. The residue was purified by flash chromatography.

9. General procedure 9 (GM 9): reductive alkylation

To a suspension of amine (1.0 eq) in a solvent such as THF, DCM or DMF are added aldehyde or ketone (5.0 eq) and AcOH (2 eq). The reaction was stirred for 15min, after which time sodium triacetoxyborohydride (3.0 eq) was added. The mixture was stirred at rt for 20h, then partitioned between EtOAc or DCM and saturated NaHCO ₃ (aqueous solution) between them. The organic layer was dried (MgSO ₄ ) Filtering and concentrating. The residue was purified by flash chromatography.

10. General method 10 (GM 10): tandem boc deprotection and Eschweiler-Clarke methylation

A solution of boc-protected amine (1.0 eq) in formic acid (10.0 eq) was stirred at 50℃for 30min, after which formaldehyde (37% in water) (2.5 eq) was added and the reaction mixture was heated to 90℃for 1-3h. The reaction mixture was concentrated. The crude product was dissolved in MeOH and passed directly through SCX and washed with MeOH (20 mL). The product was treated with 7M NH ₃ The solution in MeOH (50 mL) was eluted and concentrated. The crude product was used without further purification or purified by flash chromatography.

11. General procedure 11 (GM 11): pyridone chlorination

Pyridone (1.0 eq) was suspended in phosphorus oxychloride (large excess) and heated under reflux for 4h. The reaction mixture was evaporated and then azeotroped with toluene (×2). The residue was immediately used in the next step, taking care to exclude moisture.

12. General procedure 12 (GM 12): deprotection of 2, 4-dimethoxybenzyl group

The solution of 2, 4-dimethoxybenzyl-protected amine (1.0 eq) in TFA (10 eq.) was stirred at rt to 50 ℃ for 1h. The reaction mixture was concentrated. The resulting residue was suspended in MeOH (2 mL) and loaded onto SCX, which was rinsed with MeOH (4×5 mL). The product was treated with 1N NH ₃ A solution in MeOH (4X 5 mL) eluted. The solvent was removed in vacuo. The crude product was used without further purification or purified by flash chromatography or preparative HPLC.

13. General procedure 13 (GM 13): urethane protection

To a solution of aminopyridine (1.0 eq) and TEA (2.0 eq) in DCM (12 mL) in an ice/water bath was added methyl chloroformate (3.0 eq) and the reaction stirred at rt for 48h. Will beThe reaction mixture was diluted with DCM and washed with water (20 mL). The aqueous solution was extracted with DCM (3×80 mL) and the combined organics were dried (Na ₂ SO ₄ ) Filtering and concentrating. The crude product was triturated with EtOAc.

14. General procedure 14 (GM 14): carbamate deprotection

a. General method 14a: KOH (KOH)

A mixture of methyl carbamate (1 eq) and KOH (6 eq) in MeOH was stirred at 60℃for 12-48h. The product was isolated and purified using one of the following methods:

i) The reaction was quenched with AcOH (6.0 eq) and the mixture stirred for 5min before concentrating. The residue was passed directly through SCX in MeOH. Wash SCX with MeOH and with 7M NH ₃ The product was eluted with MeOH and lyophilized.

ii) quench the reaction with AcOH (6.0 eq) and stir the mixture for 5min before concentrating. The residue was passed directly through SCX in MeOH. Wash SCX with MeOH and with 7M NH ₃ The product was eluted with MeOH. Purification of the product by flash chromatography or preparative HPLC

iii) The reaction was quenched with AcOH (6.0 eq), concentrated, and purified by preparative HPLC.

b. General method 14b: liOH (LiOH)

To a solution of methyl carbamate (1 eq) in THF/water (10:1) was added lithium hydroxide monohydrate (3-5 eq) and the reaction stirred at 60 ℃ for 18h to 4 days. The mixture was cooled to rt and concentrated. Purification of the crude residue via flash chromatography or preparative HPLC

15. General method 15: SEM deprotection

A mixture of methanesulfonic acid (39.0 eq) and water (0.1 mL) was added dropwise to a rapidly stirred solution of indole or azaindole (1.0 eq) in DCM. The mixture was stirred at rt for 3h. The reaction mixture was diluted with DCM (10 mL) and cooled in an ice/water bath, after which it was quenched by dropwise addition of ethylenediamine (10.0 eq) and the mixture was stirred for 2h. The reaction mixture was concentrated and the crude product purified by flash chromatography.

General scheme

In which the central ring is a 6-membered aromatic or heteroaromatic ring (e.g. in the general senseIn the case of phenyl, pyridine and pyrazine shown in scheme 1, for example, by the ring comprising U and V, the same pathways and methods described in the general schemes below can be applied regardless of whether the non-R substituents (if R substituents are present) on the central ring are para or meta to each other. For example, in general scheme 3, the non-R substituents are defined as RgA-O-and-CH ₂ Those substituents of NH-RgD, and in general scheme 1, no "R substituent" is present, so "non-R substituent" is represented by, for example, rg-A-Q-and-CH ₂ NH-RgD.

General scheme 1 outlines the synthetic pathways for certain example compounds, such as those having a 6-membered central ring as defined below, and RgA, rgB and RgD refer to the various substituents required for the examples.

General scheme 1

The aryl or heteroaryl halide 1a is reacted in a solvent such as MeCN, 1, 4-dioxane, DMF or NMP at an elevated temperature of 50-100 ℃ with a suitable base at S _N Reaction with an alcohol or amine 2 under Ar (general procedure 1). The alcohol is typically reacted using a base such as cesium carbonate, potassium tert-butoxide or sodium tert-butoxide, while the amine is typically reacted using a base such as potassium carbonate, cesium carbonate or N, N-diisopropylethylamine. The aryl bromide or chloride 3 may be palladium catalyzed cyanated using conditions well known in the art (general method 2); for example by heating with Zn (CN) in a solvent such as NMP ₂ And Pd (PPh) ₃ ) ₄ Palladium catalyzed cyanation is performed. Nitrile 4 can be reduced to amine 5 under a variety of standard literature conditions well known in the art (general procedure 3); for example in the presence of Raney nickel, or in the presence of Pd/C, or alternatively in Boc ₂ With NiCl in the presence of O ₂ And NaBH ₄ Or alternatively, by hydrogenation with borane. Amine 5 is reacted with aryl bromide or chloride 6 under buchholz coupling conditions (general procedure 4). For example using BrettPhos Pd G3, brettPhos Pd G4 or RuPhos Pd G3 catalysts in, for example, t-butylThe Buchwald coupling is carried out in a solvent such as 1, 4-dioxane or THF in the presence of a base such as sodium alkoxide, cesium carbonate or potassium hexamethyldisilazane (KHMDS). Aryl bromide or chloride 6 can be prepared from readily available starting materials using methods known in the art or as described herein. Depending on the nature of RgD, a deprotection step (detailed above) may be required to obtain the example compounds.

Alternatively, where the starting material is commercially available in situ with the nitrile, e.g., 1b in general scheme 2, it may be at S as previously described _N Reaction under Ar (general procedure 1) afforded Compound 4.

General scheme 2

General schemes 3 to 5 outline the synthetic pathways for certain example compounds, such as those having a 6-membered central ring as defined below, and RgA, rgB, rgD, rgE and RgF refer to the various substituents required for the examples. RgE and RgF can be joined together to form a ring structure, as desired for an embodiment.

In general scheme 3, benzyl halide 8 (where lg=br or Cl) is reacted under typical alkylation conditions (general method 5, e.g., KOtBu-or NaH-containing DMF, or Cs-containing DMF ₂ CO ₃ Or K ₂ CO ₃ Optionally under heat) with alcohol 2 a. Alternatively, benzyl alcohol 8 (where lg=oh) may be reacted with alcohol 2a under the conditions of a Mitsunobu reaction (Mitsunobu). Typically, the pathway continues with cyanidation, reduction and Buch-Var coupling using the method as in general scheme 1. Depending on the nature of RgD, a deprotection step (detailed above) may be required to obtain the example compounds.

General scheme 3

Alternatively, for example, as shown in general scheme 4, the starting materials may be mixed with the nitrile already in place Where used together (e.g., compound 13), the amine may be prepared by reduction of the nitrile using general procedure 3. The amine may be protected in a stepwise manner with a protecting group such as a carbamate group, e.g., t-Ding Yangzhi carbamate, to produce t-butylcarbamate 14. In situ protection of amino groups may also be performed as shown in general scheme 4 (e.g., according to general methods 3d or 3 e). Protection of the amino group may facilitate purification, for example, by chromatography of intermediate 14. The protection of the amine also aids in the subsequent synthetic steps. Thus, according to general method 5, compound 14 may be found in PPh ₃ Directly reacts with alcohol 2 under the condition of light delay reaction. Alternatively, suitable leaving groups such as halide or mesylate groups may be generated using conditions well known in the art; such as using a catalyst such as DCM, THF or CCl ₄ Is chlorinated via methanesulfonate using PBr (general procedure 6) ₃ Bromination or use of CBr ₄ And PPh ₃ Bromination gives compound 15. Alkylation may then be carried out (general method 5, e.g. KO-containing ^t Bu or NaH in DMF, or Cs-containing ₂ CO ₃ Or K ₂ CO ₃ Optionally under heating). The tertiary Ding Yangzhi protecting group of the carbamate is removed from intermediate 16 using standard conditions such as TFA or HCl-containing 1, 4-dioxane (general procedure 7). Finally, the Buch-Ward coupling (general procedure 4) completes the pathway.

General scheme 4

Other analogs of compound 11 can be synthesized according to general scheme 5, such as compounds 11b and 11c.

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General scheme 5

Amide coupling (general method 8) is performed using conditions well known in the art, for example, using HATU, to form amide 18. Can be used for finishing subsequentlyBulk reduction, e.g. to contain LiAlH ₄ Or borane THF in a single step to reduce the amide and nitrile to give 11b. Alternatively, the nitrile may be reduced under hydrogenation conditions (general procedure 3) to give the complete amide, which gives compound 11c.

In certain example compounds, such as RgA, rgE, or RgF, which contain a tertiary amine, this tertiary amine can be formed prior to (general scheme 6) or during (general scheme 7) the general route.

The purchased or synthesized amine such as compound 2c can be reacted following the route and general procedure illustrated in general scheme 6.

General scheme 6

Alternatively, the primary or secondary amine may be protected with a standard protecting group (e.g., tertiary Ding Yangzhi carbamate), as shown in carbamate 2d (general scheme 7) and manipulated prior to the nitrile reduction step (general method 3).

General scheme 7

Compound 2d can be alkylated (general method 1) and cyanidated (general method 2) to form compound 22. The amine may then be deprotected and alkylated, followed in turn by deprotection with acid (general procedure 7, e.g., HCl or TFA), followed by reductive alkylation (general procedure 9) or a one pot cascade elgstrom Shi Weile-clark reaction (Eshweiler Clarke reaction) (general procedure 10).

General schemes 8 to 10 outline the synthetic pathways of certain example compounds, such as those having a 5-membered central ring as defined below, and RgD, rgG and RgH refer to the various substituents required for the examples.

Compounds having an N-substituted 5-membered central ring can be synthesized according to the general pathway outlined in general scheme 8.

General scheme 8

Using e.g. K ₂ CO ₃ Or Cs ₂ CO ₃ In a solvent such as MeCN, 1, 4-dioxane, DMF or NMP, at elevated temperature or optionally under microwave conditions (general method 5), the alkyl halide 24 is reacted with the heterocycle 1c under general alkylation conditions to effect such conversion. Nitrile 25 is reduced to amine 26 using general procedure 3, e.g., with LiAlH4, followed by reaction with aryl bromide or chloride 6 under bloch wald conditions (general procedure 4). Depending on the nature of RgD, a deprotection step (detailed above) may be required to obtain the example compounds. In certain example compounds, such as those compounds in which RgG contains a tertiary amine, this tertiary amine can be formed prior to or manipulated during the general route as described previously (e.g., general schemes 6 and 7).

In general scheme 9, heteroaryl halide 28a is reacted at S with an appropriate base such as cesium carbonate, potassium tert-butoxide or sodium tert-butoxide in a solvent such as MeCN, 1, 4-dioxane, DMF or NMP, optionally at an elevated temperature of 50-100deg.C _N Reaction under Ar (general procedure 1) with, for example, an alcohol (exemplified in general scheme 9 for compound 2 e) gives ether 29. The synthesis is accomplished via cyanidation (general method 2), reduction (hydrogenation, general method 3) and buchholz coupling (general method 4) as described previously (e.g., general schemes 1 and 3).

General scheme 9

General scheme 10 outlines the synthetic pathways for certain example compounds, such as those having a 5-membered central ring as defined below.

Conditions well known in the art, such as with N-bromosuccinimide (NBS), such as CCl, may be used ₄ Brominating heteroaryl 28b (general method 6)Bromide 33 was obtained. Alkylation may then be carried out (general method 5, e.g. KO-containing ^t Bu or NaH in DMF, or Cs-containing ₂ CO ₃ Or K ₂ CO ₃ Optionally under heat) to afford compound 34, followed by reduction (hydrogenation, general procedure 3) and buchholz coupling (general procedure 4) as previously described (e.g., general schemes 1 and 3).

General scheme 10

Geminal dimethyl, cyclopropyl and cyclobutyl can be obtained from the appropriate nitrile using literature procedures as shown in general schemes 11 to 14. RgB, rgJ, rgK, rgL and RgM refer to the various substituents required for the example compounds described herein.

General scheme 11

Nitrile 37 can be reacted with methyllithium, for example, in the presence of cerium (III) chloride in a solvent such as THF or 1, 4-dioxane at-78 ℃ to form gem-dimethylamine 38 (general scheme 11).

There are several literature conditions for the formation of cyclopropylamine from aromatic nitriles in the presence of titanium alkoxide. For example, an aromatic nitrile 39 may be reacted with titanium isopropoxide and ethylmagnesium bromide at-70℃followed by the addition of a Lewis acid such as boron trifluoride etherate (J.org. chem.2003,68,18,7133-7136) to give cyclopropylamine 40 (general scheme 12). Alternatively, cyclopropylamine 40 may be produced by reacting a metal oxide containing MeTi (O ⁱ Pr) ₃ 、LiO ⁱ And Pr, liI in the presence of THF, diethyl zinc (org. Lett.2003,5,5,753-755) was added at rt to give aromatic nitrile 39.

General scheme 12

Cyclobutyl can also be synthesized by methods reported in the literature and outlined in general schemes 13 to 14.

General scheme 13

General scheme 14

General scheme 15 overview synthesis of example compounds described herein via alkynes, e.g., to give compounds having-CH ₂ CH ₂ -compounds of the linker. For example, fluoropyridine 46 may use standard S _N Ar conditions (e.g. with alkali Cs ₂ CO ₃ General procedure 1) reaction. Alkyne 47 can then be reacted with heteroaryl bromide 48 under palladium-catalyzed sonogashira coupling (Sonogashira coupling). Alkyne 49 can be reduced by hydrogenation (general procedure 3). RgA refers to the various substituents required for the examples.

General scheme 15

Cyclopropane ring 52 may be formed as illustrated in general scheme 16 via olefin 51 utilizing simmons-smith cyclopropanation. RgB, rgD and RgN refer to the various substituents required for the compounds of the examples.

General scheme 16

The foregoing general method, such as outlined in general scheme 17 below, provides a method having, for example, -CH ₂ Synthesis of example compounds for O-ether linkers. These examples can be obtained via alcohols, for example, by obtaining protected alcohols via synthesis. Will beThe final step in the conversion of benzyl alcohol 56 to ether 57 typically requires reaction with a strong base such as NaOtBu-containing NMP at high temperature or in a microwave reactor. RgP refers to the various substituents required for the compounds of the examples.

General scheme 17

Alternatively, alcohol 60 may be synthesized from aryl bromide 58 via carbonylation and reduction outlined in scheme 18. The final step of converting the alcohol 60 to the ether 61 typically requires reaction with a strong base such as NaOtBu-containing NMP at high temperature or in a microwave reactor. RgS refers to the various substituents required for the compounds of the examples.

General scheme 18

In the example compounds described herein that contain primary or secondary amines, a protecting group strategy may be required. Alternative protecting groups may be used under different deprotection conditions such that orthogonal protecting group strategies may be applied.

For example, in the compounds defined herein that contain a 6,6 ring system as shown in general scheme 19, the protected amine can be installed by thermally and under microwave conditions reacting chloride 63 with 2, 4-dimethoxybenzyl amine using general method 1, for example, using basic conditions such as potassium carbonate or pyridine in a solvent such as NMP. RgT refers to the various substituents required for the compounds of the examples.

General scheme 19

Typically, at the end of the synthesis sequence, the 2, 4-dimethoxybenzyl protecting group is removed using undiluted TFA at 50 ℃. RgT, rjA and RjB refer to the various substituents required for the examples.

General scheme 20

Alternatively, a urethane protecting group may be used when the starting material may be used with an amine already installed. For example, as outlined in general scheme 21, an amine is reacted with methyl chloroformate using an organic base such as TEA or DIPEA in a solvent such as DCM under basic conditions to provide methyl carbamate 69.RgC refers to the various substituents required for the examples.

General scheme 21

Typically, at the end of the synthesis sequence, the methyl carbamate protecting group is deprotected at elevated temperature (typically 50 ℃) using basic conditions such as KOH or LiOH in a solvent such as 1, 4-dioxane, meCN, THF, and optionally 10% water (general scheme 22). RjC and RjD refer to the various substituents required for the examples.

General scheme 22

Another protecting group that may be used in the case of the example compounds described herein contain a 6,6 ring system is boc. Furthermore, SEM, boc and sulfonyl protecting groups may generally be used, especially where, for example, the example compounds described herein contain 5,6 ring systems. The protecting groups may then be deprotected using standard literature procedures, such as those described by t.w. greene and p.g. m.wuts in "Protective groups in organic chemistry" John Wiley and Sons, 4 th edition, 2006.

An example of the placement of an SEM protecting group is shown in general scheme 23, wherein indole 72 is treated with a base such as NaH in a solvent such as DMF followed by the addition of 2- (trimethylsilyl) ethoxymethyl chloride (general method 15).

Synthetic intermediates

Intermediate 1

(5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

Imidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

To methyl 2-aminoisonicotinate (11.0 g,0.72 mol) and NaHCO ₃ (12 g,0.14 mol) to a stirred suspension in EtOH (30 mL) was added 2-chloroacetaldehyde (50% in water) (14 mL,0.11 mol) and the resulting suspension was heated to 80℃for 5h. The reaction mixture was cooled and concentrated. The resulting solid was partitioned between water (50 mL) and DCM (50 mL), passed through a phase separator and concentrated to give the product as an orange solid (13 g, 93% yield).

[M+H] ⁺ ＝177.3

¹ H NMR(500MHz,DMSO-d6)δ3.90(3H,s),7.35(1H,dd,J＝7.1,1.7Hz),7.82(1H,d,J＝1.1Hz),8.17(2H,m),8.67(1H,dd,J＝7.1,0.9Hz)

5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

Using general procedure 3e, in the presence of EtOH (90 mL) containing 12M aqueous HCl (3.5 mL,41 mmol) at 5 bar H ₂ Imidazole was completed at 80℃over 1hAnd [1,2-a ]]Hydrogenation of methyl pyridine-7-carboxylate (7.3 g,41 mmol). The crude reaction mixture was dissolved in saturated NaHCO ₃ In (100 mL), the mixture was extracted with DCM (2X 100 mL). The organics were collected and concentrated to give the product as a brown oil (7.0 g, 71% yield).

M+H] ⁺ ＝181.2

(5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

5,6,7, 8-tetrahydroimidazo [1,2-a ] over 1h using general procedure 3b]Reduction of methyl pyridine-7-carboxylate (5.25 g,29.1 mmol). Via a path ofThe reaction mixture was filtered and the filtrate was concentrated to give the product as a brown oil (3.8 g, 83% yield).

[M+H] ⁺ ＝153.1

Intermediate 2

(3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

3-methylimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

A mixture of 2-bromo-1, 1-diethoxypropane (2081 mg,9.86 mmol) and 2M HCl (4.9 mL,9.86 mmol) was heated to 90℃and stirred for 60min. The reaction solution was cooled to rt and taken up with Na ₂ CO ₃ (8238 mg,9.86 mmol) and neutralization. Methyl 2-aminopyridine-4-carboxylate (1000 mg,6.57 mmol) and MeOH (7 mL) were added sequentially and the reaction was heated to 90℃for 18h. The solution was concentrated and purified by flash chromatography (silica gel, 30-100% etoac Petroleum ether followed by 0-20% MeOH/EtOAc) to give the product as an off-white solid (463 mg, 37% yield).

[M+H] ⁺ ＝191.0

¹ H NMR(DMSO,400MHz)δ2.51-2.53(3H,m),3.90(3H,s),7.35(1H,dd,J＝7.2,1.7Hz),7.62(1H,d,J＝1.0Hz),8.13(1H,dd,J＝1.7,1.0Hz),8.37(1H,dd,J＝7.2,1.0Hz)

3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

Methyl 3-methylimidazo [1,2-a ] pyridine-7-carboxylate (463 mg,2.43 mmol) was reacted following general method 3 e. The solvent was removed to give the product as a colorless oil (441 mg, 93% yield).

[M+H] ⁺ ＝195.1

¹ H NMR(CDCl ₃ ,400MHz)δ2.04-2.13(1H,m),2.14(3H,d,J＝1.1Hz),2.31-2.45(1H,m),2.81-2.91(1H,m),2.99(1H,dd,J＝16.5,10.2Hz),3.19(1H,ddd,J＝16.4,5.4,1.5Hz),3.64-3.72(1H,m),3.74(3H,s),3.87-4.00(1H,m),6.69(1H,d,J＝1.1Hz)

(3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

The reduction of the ester methyl 3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylate (447mg, 2.27 mmol) was performed over 70min using general method 3 b. The product was isolated as a white solid (227 mg, 60% yield) and used without further purification.

[M+H] ⁺ ＝167.0

¹ H NMR(CDCl ₃ ,400MHz)δ1.65-1.79(1H,m),2.00-2.29(6H,m),2.50(1H,dd,J＝16.5,10.7Hz),3.01(1H,ddd,J＝16.4,5.1,1.6Hz),3.59-3.74(3H,m),3.84-3.96(1H,m),6.66(1H,s)

Intermediate 3

(2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

2-methylimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

Methyl 2-aminopyridine-4-carboxylate (2.0 g,13.14 mmol) was dissolved in EtOH (20 mL) and 1-chloropropan-2-one (3.6 g,39.43 mmol) and Na were added ₂ CO ₃ (2.80 g,32.86 mmol). The suspension was stirred at 80℃for 48h. The reaction mixture was cooled to rt, concentrated, and the resulting residue was purified by flash chromatography (silica gel, 20-100% EtOAc/petroleum ether, followed by 0-20% meoh/EtOAc) to give the product as a brown solid (755 mg, 30% yield).

[M+H] ⁺ ＝191.0

2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylic acid methyl ester

Methyl 2-methylimidazo [1,2-a ] pyridine-7-carboxylate (443 mg,2.33 mmol) was semi-saturated at 70℃over 45min following general procedure 3e using 10% Pd/C CatCart. The solvent was removed in vacuo to give the product as a pale yellow oil (376 mg, 83% yield).

[M+H] ⁺ ＝195.1

(2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

Methyl ester 2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylate (376 mg,1.94 mmol) was reduced over 90min using general method 3 b. The product was isolated as a colorless oil (318 mg, 99% yield).

[M+H] ⁺ ＝167.0

¹ H NMR(CDCl ₃ ,400MHz)δ1.65-1.76(1H,m),2.05-2.16(2H,m),2.17(3H,d,J＝1.0Hz),2.42-2.52(1H,m),2.98(1H,ddd,J＝16.6,5.0,1.5Hz),3.58-3.71(3H,m),3.77-3.87(1H,m),3.99(1H,ddd,J＝12.4,5.6,2.9Hz),6.48(1H,t,J＝1.1Hz)

Intermediate 4

(4- ((1-methylpiperidin-4-yl) oxy) phenyl) methylamine

4- ((1-methylpiperidin-4-yl) oxy) benzonitrile

Following general method 1a, 1-methylpiperidin-4-ol (0.95 g,8.25 mmol) was reacted with 4-fluorobenzonitrile (1.00 g,8.26 mmol). The crude product was purified by flash chromatography (silica gel, 0-10% meoh/DCM) to give the product as a white solid (1.60 g, 87% yield).

[M+H] ⁺ ＝217.1

¹ H NMR(500MHz,DMSO-d6)δ1.58-1.69(2H,m),1.89-1.96(2H,m),2.14-2.21(5H,m),2.56-2.65(2H,m),4.51(1H,tt,J＝8.6,4.1Hz),7.09-7.15(2H,m),7.70-7.76(2H,m)。

(4- ((1-methylpiperidin-4-yl) oxy) phenyl) methylamine

Following general procedure 3e using EtOH (25 mL) with 10% Pd/C (160 mg,1.50 mmol) and sulfuric acid (1.6 mL,30.02 mmol) at 3 bar H ₂ 4- ((1-methylpiperazine) at rt Pyridin-4-yl) oxy) benzonitrile (1.59 g,7.35 mmol) was reduced for 64h. Cooling in ice/water bath while using saturated Na ₂ CO ₃ The crude product was basified (in aqueous solution) to pH 10, followed by basification with NaOH (2M) to pH 14. The aqueous layer was extracted with EtOAc (3X 50 mL), DCM (2X 40 mL) and THF (40 mL). The combined organic layers were dried (MgSO ₄ ) Filtration and concentration gave the product as a yellow oil (820 mg, 43% yield) which was used in the next step without further purification.

[M+H] ⁺ ＝221.1

¹ H NMR(500MHz,DMSO-d6)δ1.55-1.64(2H,m),1.71(2H,br.s),1.85-1.93(2H,m),2.10-2.20(5H,m),2.55-2.64(2H,m),3.62(2H,s),4.30(1H,tt,J＝8.2,4.0Hz),6.84 -6.88(2H,m),7.18-7.23(2H,m)

Intermediate 5

(4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

4- ((4-Cyanobenzyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

Following general method 5a, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.76 g,8.67 mmol) was reacted with 4- (bromomethyl) benzonitrile (1.7 g,8.67 mmol) in the presence of NaH (60% wt on mineral oil) (0.35 g,8.75 mmol) for 18h. The crude product was purified by flash chromatography (silica gel, 0-50% etoac/isohexane) to give the product as a colourless gum (1.65 g, 57% yield) which was allowed to stand.

[M+H] ⁺ ＝261.1

¹ H NMR(500MHz,DMSO-d6)δ1.40(9H,s),1.40-1.46(2H,m),1.80-1.86(2H,m),3.00-3.10(2H,m),3.55-3.67(3H,m),4.62(2H,s),7.52-7.55(2H,m),7.80-7.83(2H,m)。

4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile

Following general method 10, formic acid (2.0 mL,52.1 mmol) containing tert-butyl 4- ((4-cyanobenzyloxy) piperidine-1-carboxylate (1.60 g,5.06 mmol) was reacted with formaldehyde (37% in water) (0.80 mL,11.0 mmol) at 90℃for 2h. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless oil (980 mg, 82% yield).

¹ H NMR(500MHz,DMSO-d6)δ1.47-1.56(2H,m),1.82-1.89(2H,m),1.97-2.05(2H,m),2.13(3H,s),2.55-2.63(2H,m),3.38(1H,tt,J＝8.6,4.1Hz),4.59(2H,s),7.51-7.54(2H,m),7.80-7.83(2H,m)。

(4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

/>

Nitrile 4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile (380 mg,1.65 mmol) was reduced according to general method 3b for 18h. The product was isolated as a colourless solid (380 mg, 93% yield) and used without further purification.

[M+H] ⁺ ＝235.4

¹ H NMR (500 MHz, DMSO-d 6) δ1.43-1.54 (2H, m), 1.74-1.87 (2H, m), 1.94-2.01 (2H, m), 2.12 (3H, s), 2.55-2.62 (2H, m), 3.38-3.43 (1H, m), 3.69 (2H, d, J=4.1 Hz), 4.45 (2H, s), 7.22-7.25 (2H, m), 7.27-7.30 (2H, m). NH was not observed ₂ 。

Intermediate 6

(2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

4- ((4-bromo-3-fluorobenzyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

Using general procedure 5a, 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.76 g,8.67 mmol) was reacted with 1-bromo-4- (bromomethyl) -2-fluorobenzene (1.7 g,8.67 mmol) at rt for 2h. Subsequently saturated NaHCO is added ₃ (aqueous solution) (100 mL) the reaction mixture was extracted with TBME (2X 100 mL). The organic phases were combined and dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-50% EtOAc/isohexane) to give the product as a thick colorless oil (1.1 g, 56% yield).

[M-boc+H] ⁺ ＝332.3/334.3

¹ H NMR(500MHz,DMSO-d6)δ1.40(9H,s),1.41-1.44(2H,m),1.76-1.87(2H,m),2.98-3.11(2H,m),3.52-3.59(1H,m),3.59-3.68(2H,m),4.52(2H,s),7.15(1H,d,J＝8.2,1.9Hz),7.33(1H,d,J＝9.8,1.9Hz),7.68(1H,t,J＝7.8Hz)。

19F NMR(471MHz,DMSO)δ-108.62。

4- ((4-bromo-3-fluorobenzyl) oxy) -1-methylpiperidine

Following general method 10, tert-butyl 4- ((4-bromo-3-fluorobenzyl) oxy) piperidine-1-carboxylate (1.10 g,2.83 mmol) was reacted at 90℃for 3h. After elution via SCX, the product was isolated as a colourless gum (696 mg, 79% yield).

[M+H] ⁺ ＝302.2/304.2

¹ H NMR(500MHz,DMSO-d6)δ1.45 -1.55(2H,m),1.81-1.88(2H,m),1.95-2.05(2H,m),2.13(3H,s),2.55-2.62(2H,m),3.34-3.41(1H,m),4.49(2H,s),7.14(1H,d,J＝8.2,1.9Hz),7.31(1H,d,J＝9.8,1.9Hz),7.67(1H,t,J＝7.8Hz)。

¹⁹ F NMR(471MHz,DMSO)δ-108.68。

2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile

Using general procedure 2, 4- ((4-bromo-3-fluorobenzyl) oxy) -1-methylpiperidine (350 mg,1.16 mmol) was reacted for 16h. By flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless oil (230 mg, 79% yield).

[M+H] ⁺ ＝249.4

¹ H NMR(500MHz,DMSO-d6)δ1.47-1.57(2H,m),1.82-1.90(2H,m),1.96-2.07(2H,m),2.15(3H,s),2.56-2.64(2H,m),3.35-3.45(1H,m),4.61(2H,s),7.37(1H,dd,J＝8.0,1.4Hz),7.45(1H,dd,J＝10.5,1.3Hz),7.88-7.93(1H,m)。

(2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

The nitrile 2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile (220 mg,0.89 mmol) was reduced at rt following general procedure 3b for 3h. The product was isolated as a colourless solid (206 mg, 88% yield) and was used without further purification.

[M+H] ⁺ ＝253.4

¹ H NMR(500MHz,DMSO-d6)δ1.44 -1.55(2H,m),1.78(2H,s),1.78-1.88(2H,m),1.93-2.03(2H,m),2.13(3H,s),2.54-2.62(2H,m),3.33 -3.39(1H,m),3.72(2H,s),4.47(2H,s),7.05(1H,dd,J＝11.1,1.6Hz),7.09-7.14(1H,m),7.44(1H,t,J＝7.9Hz)。

Intermediate 7

(6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine

6- ((1-methylpiperidin-4-yl) methoxy) nicotinonitrile

/>

Using general procedure 1a, (1-methylpiperidin-4-yl) methanol (300 mg,2.32 mmol) was reacted with 6-fluoronicotinonitrile (284 mg,2.32 mmol) for 20h. The crude reaction mixture was passed directly through SCX and washed with MeOH. By using a catalyst containing 7M NH ₃ The desired product was eluted with MeOH. The resulting mixture was concentrated and purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow solid (250 mg, 42% yield).

[M+H] ⁺ ＝232.3

¹ H NMR(500MHz,DMSO-d6)δ1.18-1.36(2H,m),1.63-1.73(3H,m),1.79-1.91(2H,m),2.15(3H,s),2.72-2.82(2H,m),4.19(2H,d,J＝6.2Hz),7.00(1H,dd,J＝8.7,0.8Hz),8.14(1H,dd,J＝8.7,2.4Hz),8.68(1H,dd,J＝2.4,0.8Hz)。

(6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine

The reduction of nitrile 6- ((1-methylpiperidin-4-yl) methoxy) nicotinonitrile (100 mg,0.43 mmol) was carried out over 2h using a Raney nickel cartridge using general method 3 a. The product was isolated as a white solid (78 mg, 74% yield).

[M+H] ⁺ ＝236.4

¹ H NMR (500 mhz, dmso-d 6) δ1.16-1.34 (2H, m), 1.61-1.74 (3H, m), 1.78-1.87 (2H, m), 2.14 (3H, s), 2.70-2.81 (2H, m), 3.64 (2H, s), 4.07 (2H, d, j=6.2 Hz), 6.74 (1H, d, j=8.4 Hz), 7.66 (1H, dd, j=8.5, 2.5 Hz), 8.03 (1H, d, j=2.4 Hz) (no NH is observed ₂ )。

Intermediate 8

5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine

6- (((1-methylpiperidin-4-yl) methyl) amino) nicotinonitrile

Following general method 1d, 6-fluoronicotinonitrile (100 mg,0.82 mmol) was reacted with (1-methylpiperidin-4-yl) methylamine (120 mg,0.94 mmol) using DIPEA (0.30 mL,1.7 mmol) as base at 80℃for 30min. The mixture was cooled to rt and concentrated. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ The crude product was purified with MeOH/EtOAc) to give the product as a white solid (154 mg, 78% yield).

[M+H] ⁺ ＝231.3

¹ H NMR(500MHz,DMSO-d 6)1.10-1.24(2H,m),1.43-1.52(1H,m),1.60-1.69(2H,m),1.74-1.83(2H,m),2.12(3H,s),2.68-2.78(2H,m),3.12-3.25(2H,m),6.55(1H,dd,J＝8.9,0.8Hz),7.57-7.70(2H,m),8.37(1H,dd,J＝2.3,0.7Hz)。

5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine

Following general method 3a, 6- (((1-methylpiperidin-4-yl) methyl) amino) nicotinonitrile (100 mg,0.43 mmol) was reduced over 2h using raney nickel. The mixture was concentrated to give the product as a colorless oil (77 mg, 72% yield).

[M+H] ⁺ ＝235.3

¹ H NMR (500 MHz, DMSO-d 6) 1.09-1.20 (2H, m), 1.41-1.52 (1H, m), 1.61-1.69 (2H, m), 1.73-1.81 (2H, m), 2.12 (3H, s), 2.68-2.78 (2H, m), 3.05-3.12 (2H, m), 3.50 (2H, s), 6.32 (1H, t, J=5.8 Hz), 6.41 (1H, d, J=8.5 Hz), 7.32 (1H, dd, J=8.5, 2.4 Hz), 7.84 (1H, d, J=2.3 Hz), no two exchangeable protons are observed.

Intermediate 9

(2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methylamine

2- ((1-methylpiperidin-4-yl) methoxy) isonicotinic acid nitrile

Following general procedure 1a, KO was used ^t Bu (919 mg,8.19 mmol) was used as a base and (1-methylpiperidin-4-yl) methanol (529 mg,4.10 mmol) was reacted with 2-fluoroisonicotinic nitrile (500 mg,4.10 mmol) for 18h. By flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless oil (451 mg, 45% yield).

[M+H] ⁺ ＝232.1

¹ H NMR(500MHz,DMSO-d6)δ1.21-1.35(2H,m),1.64-1.74(3H,m),1.79-1.89(2H,m),2.15(3H,s),2.72-2.80(2H,m),4.15(2H,d,J＝6.2Hz),7.35-7.38(1H,m),7.39(1H,dd,J＝5.2,1.3Hz),8.39(1H,dd,J＝5.2,0.9Hz)。

(2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methylamine

Nitrile 2- ((1-methylpiperidin-4-yl) methoxy) isonicotinic nitrile (200 mg,0.865 mmol) was reduced according to general method 3a for 2h. The solvent was removed in vacuo to give the product as a colourless solid (205 mg, 97% yield).

[M+H] ⁺ ＝236.1

¹ H NMR(500MHz,DMSO-d6)δ1.18-1.35(2H,m),1.68-1.72(3H,m),1.78-1.91(2H,m),2.15(3H,s),2.59(2H,s),2.70-2.83(2H,m),3.70(2H,s),4.08(2H,d,J＝6.1Hz),6.73-6.80(1H,m),6.91(1H,dd,J＝5.2,1.4Hz),8.02(1H,d,J＝5.2Hz)。

Intermediate 10

4- (aminomethyl) -N- [ (1-methyl-4-piperidinyl) methyl ] pyridin-2-amine

2- [ (1-methyl-4-piperidinyl) methylamino ] pyridine-4-carbonitrile

Following general method 1b, (1-methylpiperidin-4-yl) methylamine (231 mg,1.80 mmol) was reacted with 2-fluoropyridine-4-carbonitrile (200 mg,1.64 mmol) at 60℃for 48h. After water treatment, the crude product was purified by flash chromatography (amino-D, 0-100% EtOAc/petroleum ether) to give the product as a yellow oil (190 mg, 44% yield) which solidified on standing.

[M+H] ⁺ ＝231.0

¹ H NMR(CDCl ₃ 400 MHz) δ1.29-1.45 (2H, m), 1.52-1.63 (1H, m), 1.74-1.81 (3H, m should be 2H, partially obscured by water), 1.92 (2H, td, j=11.8, 2.6 Hz), 2.27 (3H, s), 2.87 (2H, dt, j=12.1, 3.8 Hz), 3.19 (2H, dd, j=6.8, 6.0 Hz), 4.88 (1H, s), 6.55 (1H, t, j=1.1 Hz), 6.72 (1H, dd, j=5.1, 1.3 Hz), 8.18 (1H, dd, j=5.1, 0.9 Hz).

4- (aminomethyl) -N- [ (1-methyl-4-piperidinyl) methyl ] pyridin-2-amine

Following general procedure 3e, nitrile 2- [ (1-methyl-4-piperidinyl) methylamino was reduced in the presence of palladium hydroxide on carbon (70 mg,0.09 mmol) and 10% Pd/C (98 mg,0.09 mmol) for 7h]Pyridine-4-carbonitrile (120 mg,0.46 mmol). Via a path ofFiltering the mixture and concentrating to obtain a transparent productSemisolid product (110 mg, 72% yield).

[M+H] ⁺ ＝235.1

Intermediate 11

4- (((4- (aminomethyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

4- (((4-cyanopyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

Following general method 1b, tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (353 mg,1.64 mmol) was reacted with 2-fluoroisonicotinic nitrile (200 mg,1.64 mmol) for 18h. The reaction mixture was cooled to rt and diluted with water (10 mL). The crude product was extracted into DCM (2X 25 mL) and dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 5-100% EtOAc/petroleum ether) to give the product as a pale yellow oil (500 mg, 96% yield).

[M-boc+H] ⁺ ＝218.1

¹ H NMR(400MHz,CDCl ₃ )δ1.21-1.32(2H,m),1.47(9H,s),1.80(2H,d,J＝12.9Hz),1.92-2.02(1H,m),2.75(2H,t,J＝11.8Hz),4.09-4.20(4H,m),6.99(1H,d,J＝0.9Hz),7.07(1H,dd,J＝5.1,1.3Hz),8.28(1H,d,J＝5.0Hz)ppm。

Following general method 3a, nitrile 4- (((4-cyanopyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (500 mg,1.58 mmol) was reduced using raney nickel. The solvent was removed in vacuo to give the product as a colourless oil (497 mg, 98% yield).

[M+H] ⁺ ＝322.1

¹ H NMR(CDCl ₃ ,400MHz)δ1.25(2H,qd,J＝12.4,4.4Hz),1.46(9H,s),1.73-1.83(2H,m),1.89-2.00(1H,m),2.33(2H,br s),2.73(2H,t,J＝12.8Hz),3.86(2H,s),4.04-4.19(4H,m),6.65-6.75(1H,m),6.77-6.88(1H,m),8.07(1H,dd,J＝5.3,0.7Hz)ppm

Intermediate 12

1- (5- (((4- (aminomethyl) pyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1] hept-2-yl) ethan-1-one

5- (((4-cyanopyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

Following general method 1b, tert-butyl 5- (hydroxymethyl) -2-azabicyclo [2.2.1] heptane-2-carboxylate (500 mg,2.20 mmol) was reacted with 2-fluoroisonicotinic nitrile (279 mg,2.20 mmol) for 72h. The reaction mixture was filtered and purified by flash chromatography (silica gel, 0-60% EtOAc/isohexane) to give the product as a colorless solid (1.01 g, 65% yield).

[M+Na] ⁺ ＝352.2

¹ H NMR(500MHz,DMSO-d6)1.10-1.19(1H,m),1.39(9H,s),1.51-1.61(1H,m),1.63-1.73(1H,m),1.80-1.91(1H,m),2.45-2.49(1H,m),2.54-2.58(1H,m),3.01-3.11(1H,m),3.20-3.25(1H,m),4.02(1H,d,J＝14.2Hz),4.12-4.20(1H,m),4.32-4.42(1H,m),7.36-7.38(1H,m),7.41(1H,dd,J＝5.2,1.4Hz),8.40(1H,dd,J＝5.2,0.8Hz)。

2- ((2-azabicyclo [2.2.1] hept-5-yl) methoxy) isonicotinic acid nitrile

Boc deprotection of tert-butyl 5- (((4-cyanopyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1] heptane-2-carboxylate (337 mg,1.02 mmol) was performed following general method 7 b. After elution via SCX, the product was isolated (233 mg, 94% yield) and used without further purification.

[M+H] ⁺ ＝230.1

¹ H NMR (500 MHz, DMSO-d 6) 0.95-1.03 (1H, m), 1.41-1.51 (2H, m), 1.72-1.79 (1H, m), 2.27-2.40 (2H, m), 2.57-2.62 (1H, m), 2.79 (1H, d, J=9.9 Hz), 3.24-3.27 (1H, m), 4.28 (1H, dd, J=10.7, 9.1 Hz), 4.40 (1H, dd, J=10.7, 6.6 Hz), 7.37 (1H, s), 7.39 (1H, dd, J=5.3, 1.4 Hz), 8.40 (1H, d, J=5.2 Hz), NH was not observed

2- ((2-acetyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) isonicotinic acid nitrile

Treatment of 2- ((2-azabicyclo [ 2.2.1) with DIPEA (400. Mu.L, 2.30 mmol) and acetic anhydride (100. Mu.L, 1.06 mmol)]A solution of hept-5-yl) methoxy isonicotinic acid nitrile (233 mg,1.02 mmol) in DCM (5 mL) was then stirred at rt for 18h. The mixture was treated with 1M HCl (20 mL) and the layers were separated. The aqueous layer was extracted with DCM (2X 5 mL). The combined organics were dried (Na ₂ SO ₄ ) Filtration and concentration gave the product as a yellow gum (280 mg, 99% yield).

[M+H] ⁺ ＝272.1

The reduction of nitrile 2- ((2-acetyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) isonicotinic nitrile (280 mg,1.03 mmol) was performed over 3h using Raney nickel following general method 3 a. The resulting solution was concentrated to give the product as a colorless solid (250 mg, 86% yield).

[M+H] ⁺ ＝276.2

Intermediate 13

(1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methylamine

4- (2- (4-cyano-1H-pyrazol-1-yl) ethyl) piperidine-1-carboxylic acid tert-butyl ester

Following general method 5b, tert-butyl 4- (2-bromoethyl) piperidine-1-carboxylate (800 mg,2.74 mmol) was reacted with 1H-pyrazole-4-carbonitrile (255 mg,2.74 mmol) and K-containing ₂ CO ₃ (720 mg,5.21 mmol) of NMP (4 mL). The crude product was purified by flash chromatography (silica gel, 0-100% etoac/isohexane) to give the product as a colourless gum (740 mg, 80% yield).

[M+H] ⁺ ＝248.2

1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazole-4-carbonitrile

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Tert-butyl 4- (2- (4-cyano-1H-pyrazol-1-yl) ethyl) piperidine-1-carboxylate (0.85 g,2.79 mmol) was reacted at 90℃for 2H using general method 10. The crude product was purified by flash chromatography (silica gel, 0-10% MeOH/DCM) to give the product as a colourless gum (254 mg, 40% yield).

¹ H NMR(500MHz,DMSO-d6)δ1.04-1.20(3H,m),1.57-1.65(2H,m),1.68-1.74(2H,m),1.74-1.81(2H,m),2.13(3H,s),2.69 -2.74(2H,m),4.20(2H,t,J＝7.3Hz),8.05(1H,s),8.59(1H,s)

(1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methylamine

Nitrile 1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazole-4-carbonitrile (154 mg,0.71 mmol) was reduced according to general method 3b and reacted for 18H. The product was isolated as a colourless gum (135 mg, 80% yield) and used without further purification.

¹ H NMR(500MHz,DMSO-d6)δ1.04-1.19(3H,m),1.45-1.69(6H,m),1.69-1.79(2H,m),2.11(3H,s),2.66-2.73(2H,m),3.55(2H,s),4.05(2H,t,J＝7.3Hz),7.30(1H,s),7.51-7.55(1H,m)。

Intermediate 14

(2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methylamine

2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) isonicotinic acid nitrile

Following general method 1b, (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol (200 mg,1.31 mmol) is reacted with 2-fluoroisonicotinic nitrile (321 mg,2.63 mmol) for 18h. After water treatment, the crude product was purified by flash chromatography (silica gel, 0-20% MeOH/DCM) to give the product as an orange oil (214 mg, 61% yield).

[M+H] ⁺ ＝255.0

Nitrile 2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) isonicotinic nitrile (214 mg,0.84 mmol) was reduced over 3h using Raney nickel according to general method 3 a. The solvent was removed in vacuo to give the product as an orange oil (216 mg, 99% yield).

[M+Na] ⁺ ＝259.0

Intermediate 15

(6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methylamine

6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) nicotinonitrile

Following general procedure 1b, (5, 6,7, 8-tetrahydroimidazo [1,2-a]Pyridin-7-yl) methanol (890 mg,5.85 mmol) was reacted with 6-fluoronicotinonitrile (514 mg,5.85 mmol) for 5h. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-10% (containing 0.7 NH) ₃ MeOH)/DCM) to give the product as a light brown solid (723 mg, 44% yield).

[M+H] ⁺ ＝255.3

¹ H NMR(500MHz,DMSO-d6)δ1.68-1.80(1H,m),2.10-2.18(1H,m),2.35-2.45(1H,m),2.51-2.55(1H,m),2.94(1H,ddd,J＝16.2,5.0,1.5Hz),3.84-3.94(1H,m),4.04-4.13(1H,m),4.37(2H,d,J＝6.6Hz),6.81(1H,d,J＝1.2Hz),7.00(1H,d,J＝1.2Hz),7.06(1H,dd,J＝8.7,0.8Hz),8.18(1H,dd,J＝8.7,2.4Hz),8.71(1H,dd,J＝2.4,0.8Hz)

Reduction of 6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) nicotinonitrile (200 mg,0.79 mmol) was performed over 2h using raney nickel using general method 3 a. The reaction mixture was concentrated to give the product as a clear yellow oil (190 mg, 87% yield).

[M+H] ⁺ ＝259.0

¹ H NMR (500 MHz, DMSO-d 6) delta 1.65-1.78 (1H, m), 2.09-2.17 (1H, m), 2.32-2.43 (1H, m), 2.45-2.53 (1H, m), 2.93 (1H, ddd, J=16.2, 5.1,1.6 Hz), 3.65 (2H, s), 3.84-3.94 (1H, m), 4.04-4.13 (1H, m), 4.22-4.27 (2H, m), 6.78-6.83 (2H, m), 6.99 (1H, d, J=1.3 Hz), 7.69 (1H, dd, J=8.5, 2.5 Hz), 8.06 (1H, d, J=2.5 Hz), (not found NH) ₂ )。

Intermediate 16

5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole

Following general procedure 5a, 5-bromo-1H-indole (1.0 g,5.1 mmol) was reacted with SEM-Cl (5.7 mmol) at rt for 1H. Adding saturated NH ₄ Aqueous Cl (30 mL) and extracted with TBME (30 mL). The organics were washed with brine/water (1:1, 30 mL) and brine (2X 30 mL) then dried (MgSO) ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-10% TBME/hexane) to give the product as a colourless gum (1.13 g, 64% yield). ¹ HNMR(500MHz,DMSO-d6)-0.10(9H,s),0.77-0.83(2H,m),3.40-3.46(2H,m),5.55(2H,s),6.48(1H,dd,J＝3.2,0.8Hz),7.29(1H,dd,J＝8.7,2.0Hz),7.52-7.55(2H,m),7.76(1H,d,J＝1.9Hz)。

Intermediate 17

5-bromo-3-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole

Following general method 6b, DCM (25 mL) containing 5-bromo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indole (1.13 g,3.46 mmol) was reacted with NCS (500 mg,3.74 mmol) at rt for 18H. After water treatment, the crude material was purified by flash chromatography (silica gel, 0-5% EtOAc/isohexane) to give the product as a yellow gum (830 mg, 60% yield).

¹ H NMR(500MHz,DMSO-d6)-0.10(9H,s),0.77-0.82(2H,m),3.42-3.47(2H,m),5.54(2H,s),7.41(1H,dd,J＝8.7,2.0Hz),7.62(1H,dd,J＝8.7,0.6Hz),7.66(1H,dd,J＝2.0,0.5Hz),7.79(1H,s)。

Intermediate 18

5-bromo-3-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridine

Following general procedure 5a, 5-bromo-3-chloro-1H-pyrrolo [2,3-b]Pyridine (480 mg,2.07 mmol) was reacted with (2- (chloromethoxy) ethyl) trimethylsilane (0.4 mL,2.28 mmol) for 2h. The reaction was quenched with water (2 mL) and diluted with EtOAc (40 mL). The organic layer was washed with water (20 mL), 1M HCl (aq) (20 mL), 1:1 water/brine (20 mL), and brine (20 mL), dried (MgSO ₄ ) Filtered and concentrated. The crude product was purified by flash chromatography (silica gel, 0-100% etoac/isohexane) to give the product as an orange oil (485 mg, 60% yield).

[M+H] ⁺ ＝363.0

¹ H NMR(500MHz,DMSO-d6)δ-0.10(9H,s),0.81(2H,t,J＝7.9Hz),3.51(2H,t,J＝7.9Hz),5.60(2H,s),7.98 -8.01(1H,m),8.20 -8.24(1H,m),8.44 -8.47(1H,m)

Intermediate 19

(6-bromoisoquinolin-1-yl) carbamic acid tert-butyl ester

Boc at 40℃with Boc ₂ A solution of 6-bromoisoquinolin-1-amine (0.50 g,2.20 mmol) in tBuOH (10 mL) was treated with O (0.49 g,2.20 mmol) and heated to 70℃for 18h. The reaction mixture was concentrated and the crude product purified by flash chromatography (silica gel, 0-100% EtOAc/isohexane) to give the product as a colorless solid (457 mg, 60% yield).

[M+H] ⁺ ＝322.9

¹ H NMR(500MHz,DMSO-d6)δ1.48(9H,s),7.64(1H,d,J＝5.7Hz),7.79(1H,d,J＝8.9Hz),8.00(1H,d,J＝9.0Hz),8.27(1H,s),8.31(1H,d,J＝5.7Hz),9.85(1H,s)。

Intermediate 20

(6-bromoisoquinolin-1-yl) (methyl) carbamic acid tert-butyl ester

A mixture of tert-butyl (6-bromoisoquinolin-1-yl) carbamate (150 mg,0.46 mmol) and iodomethane (35. Mu.L, 0.56 mmol) in THF (2 mL) was cooled in an ice/water bath. NaH (60% in mineral oil) (23 mg,0.60 mmol) was added and the mixture was warmed to rt and stirred for 18h. The reaction was quenched with MeOH (0.5 mL) and concentrated. The crude mixture was dissolved in water (20 mL) and extracted into EtOAc (2X 20 mL) and the combined organic layers were dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-50% EtOAc/isohexane) to give the product as an off-white solid (104 mg, 64% yield).

[M+H] ⁺ ＝281.1/283.1

¹ H NMR(500MHz,DMSO-d6)δ1.22(9H,s),3.29(3H,s),7.78(1H,d,J＝5.7Hz),7.81-7.88(2H,m),8.35(1H,d,J＝1.9Hz),8.42(1H,d,J＝5.7Hz)。

Intermediate 21

(5-bromoisoquinolin-1-yl) carbamic acid tert-butyl ester

With Boc ₂ A suspension of 5-bromoisoquinolin-1-amine (700 mg,3.14 mmol) in tBuOH (6 mL) was treated with O (1.5 g,6.90 mmol) and heated to 70℃for 18h. The reaction mixture was concentrated, then dissolved in MeOH (30 mL) and K was added ₂ CO ₃ (860 mg,6.22 mmol) and the reaction mixture was heated at 70℃for 1h. Cooling to rt, filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 100% DCM) to give the product as a yellow solid (700 mg, 52% yield).

[M-boc+H] ⁺ ＝323.0

Intermediate 22

(6-bromoisoquinolin-3-yl) carbamic acid tert-butyl ester

With Boc ₂ A solution of 6-bromoisoquinolin-3-amine (1.0 g,4.48 mmol) in tBuOH (10 mL) was treated with O (1.47 g,6.72 mmol) and heated to 70℃for 18h. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 5-100% THF/isohexane) to give the product as a brown solid (825 mg, 54% yield).

[M+H] ⁺ ＝323.0

¹ H NMR(500MHz,DMSO-d6)δ1.51(9H,s),7.59(1H,dd,J＝8.7,1.9Hz),7.97(1H,d,J＝8.7Hz),8.12 -8.13(1H,m),8.17-8.18(1H,m),9.09-9.10(1H,m),9.96(1H,s)。

Intermediate 23

(6-bromoisoquinolin-1-yl) carbamic acid methyl ester

Following general method 13, 6-bromoisoquinolin-1-amine (1.50 g,6.72 mmol) was protected. The crude material was suspended in water (100 mL) and stirred for 30min, after which it was collected by filtration and dried overnight in a vacuum oven to give the product as an off-white solid (1.12 g, 44% yield).

[M+H] ⁺ ＝281.1

¹ H NMR(500MHz,DMSO-d6)3.70(3H,s),7.58-7.72(1H,m),7.79(1H,d,J＝9.0,2.0Hz),8.04(1H,d,J＝9.1Hz),8.25-8.30(1H,m),8.33(1H,d,J＝5.8Hz),10.18(1H,s)

Intermediate 24

(6-bromo-4-chloroisoquinolin-1-yl) carbamic acid methyl ester

Methyl N- (6-bromo-1-isoquinolinyl) carbamate (100 mg,0.36 mmol) was dissolved in chloroform (5 mL), NCS (52 mg,0.39 mmol) was added, and the reaction stirred at reflux for 18h. Addition of saturated NaHCO to the reaction ₃ (aqueous solution) (30 mL) and washed with DCM (30 mL), dried (Na) ₂ SO ₄ ) And concentrated. The crude product was purified by flash chromatography (silica gel, 0-80% etoac/petroleum ether) to give the product as a pale beige solid (74 mg, 59% yield).

[M+H] ⁺ ＝316.8/318.7

¹ H NMR(CDCl ₃ ,400MHz)δ3.84(3H,s),7.36(1H,s),7.75(1H,dd,J＝9.0,1.9Hz),7.93(1H,d,J＝9.0Hz),8.37(2H,d,J＝4.9Hz)

Intermediate 25

(5-bromoisoquinolin-1-yl) carbamic acid methyl ester

Following general method 13, 5-bromoisoquinolin-1-amine (1.12 g,5.02 mmol) was protected. The product was dried under high vacuum to give the product (838 mg, 56% yield).

[M+H]+＝281.1

Intermediate 26

6-chloro-N- (2, 4-dimethoxybenzyl) -2, 7-naphthyridin-1-amine

Following general procedure 1c, 1, 6-dichloro-2, 7-naphthyridine (200 mg,1.00 mmol) was protected in NMP (1 mL) at 100deg.C for 1h. The reaction mixture was dissolved in water (20 mL) and MeOH (20 mL) and filtered to give the product as an orange solid (212 mg, 45% yield).

[M+H] ⁺ ＝330.1

¹ H NMR(500MHz,DMSO-d6)3.73(3H,s),3.83(3H,s),4.63(2H,d,J＝5.4Hz),6.44(1H,dd,J＝8.4,2.4Hz),6.58(1H,d,J＝2.3Hz),6.84(1H,d,J＝5.8Hz),7.12(1H,d,J＝8.3Hz),7.77(1H,s),8.05(1H,d,J＝5.8Hz),8.35(1H,t,J＝5.6Hz),9.50(1H,s)

Intermediate 27

5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine

To a solution of 5-bromo-1-chloroisoquinoline (0.5 g,2.06 mmol) in pyridine (3 mL) was added 2, 4-dimethoxybenzylamine (0.69 g,4.12 mmol). The reaction was heated in CEM microwaves at 150℃for 1h. The mixture was diluted with DCM (20 mL) and water (20 mL). The aqueous layer was re-extracted with DCM (3X 10 mL) and the combined organics were washed with brine (20 mL). The organic layer was dried (Na ₂ SO ₄ ) Filtration and concentration gave the crude product. Purification by flash chromatography (silica gel, 20-50% EtOAc/petroleum ether) afforded the product as a pale yellow oil (276 mg, 50% yield).

[M+H] ⁺ ＝373.0/375.0

¹ H NMR(DMSO-d ₆ ,400MHz)δ3.71(3H,d,J＝2.6Hz),3.82(3H,d,J＝2.8Hz),4.62(2H,d,J＝5.4Hz),6.41(1H,dd,J＝8.5,2.5Hz),6.56(1H,d,J＝2.6Hz),6.94-7.14(2H,m),7.42(1H,t,J＝8.0Hz),7.96(3H,ddd,J＝16.4,7.1,3.2Hz),8.38(1H,d,J＝8.2Hz)。

Intermediate 28

6-bromo-N- (2, 4-dimethoxybenzyl) -4-fluoroisoquinolin-1-amine

6-bromo-1-chloro-4-fluoroisoquinoline

A solution of 6-bromo-2H-isoquinolin-1-one (8.0 g,35.7 mmol) and SelectFluor (15.2 g,42.8 mmol) in MeCN (100 mL) and MeOH (100 mL) was heated at 50deg.C for 1H. The reaction mixture was evaporated and reacted with benzyltriethylammonium chloride (820 mg,3.6 mmol) and phosphorus oxychloride (50 mL) in 1, 2-dichloroethane (200 mL) using general method 11. The reaction mixture was evaporated and the residue partitioned between DCM (500 mL) and water (500 mL). The organic layer was washed with water (300 mL), brine (300 mL), and dried (MgSO ₄ ) And evaporated. The crude material was purified by flash chromatography (silica gel, 5% EtOAc/petroleum ether) to give the product as an off-white solid (6.88 g, 74% yield).

[M+H] ⁺ ＝260.0

¹ H NMR(500MHz,CDCl ₃ )δ8.27(d,J＝1.9Hz,1H),8.21-8.16(m,2H),7.84(dd,J＝9.1,1.9Hz,1H)。

¹⁹ F NMR(471MHz,CDCl ₃ )δ-139.8(s)。

6-bromo-N- (2, 4-dimethoxybenzyl) -4-fluoroisoquinolin-1-amine

Following general method 1c, 6-bromo-1-chloro-4-fluoroisoquinoline (6.88 g,26.4 mmol) was reacted with 1-methyl-2-pyrrolidone (100 mL) containing 2, 4-dimethoxybenzylamine (5.95 mL,39.6 mmol) at 100deg.C for 48h. The crude product was purified by flash chromatography (silica gel, 0-20% EtOAc/petroleum ether) to give the product as an off-white solid (3.2 g, 31% yield).

[M-H] ^- ＝389.2

¹ H NMR(500MHz,DMSO)δ8.35(dd,J＝9.0,2.2Hz,1H),7.98(d,J＝2.0Hz,1H),7.90-7.70(m,3H),7.07(d,J＝8.3Hz,1H),6.55(d,J＝2.4Hz,1H),6.41(dd,J＝8.5,2.4Hz,1H),4.56(d,J＝5.5Hz,2H),3.82(s,3H),3.72(s,3H)。

¹⁹ F NMR(471MHz,DMSO)δ-157.4(s)。

Intermediate 29

5-bromo-N- (2, 4-dimethoxybenzyl) -4-fluoroisoquinolin-1-amine

5-bromo-1-chloro-4-fluoroisoquinoline

A solution of 5-bromo-2H-isoquinolin-1-one (9.0 g,40.2 mmol) and SelectFluor (17.1 g,48.2 mmol) in MeCN (120 mL) and MeOH (120 mL) was heated at 50deg.C for 3H. The reaction mixture was evaporated and reacted using general method 11 in 1, 2-dichloroethane (200 mL) with benzyl triethylammonium chloride (915 mg,4.0 mmol) and phosphorus oxychloride (45 mL) at 90 ℃ for 24h. The reaction mixture was evaporated and the residue partitioned between DCM (500 mL) and water (500 mL). The organic layer was washed with water (300 mL) and brine (300 mL), dried (MgSO ₄ ) And evaporated. The crude material was purified by flash chromatography (silica gel, 0-30% EtOAc/petroleum ether) to give the product as an off-white solid (5.70 g, 55% yield).

[M+H] ⁺ ＝261.9

¹ H NMR(500MHz,CDCl ₃ )δ8.39-8.33(m,1H),8.23(d,J＝4.0Hz,1H),8.12 -8.06(m,1H),7.57(t,J＝8.0Hz,1H)。

5-bromo-N- (2, 4-dimethoxybenzyl) -4-fluoroisoquinolin-1-amine

Following general method 1c, 5-bromo-1-chloro-4-fluoroisoquinoline (5.70 g,21.9 mmol) was reacted with 1-methyl-2-pyrrolidone (80 mL) containing 2, 4-dimethoxybenzylamine (4.93 mL,32.8 mmol) at 100deg.C for 48h. The crude product was purified by flash chromatography (silica gel, 0-30% EtOAc/petroleum ether) to give the product as a white solid (1.05 g, 12% yield).

¹ H NMR(500MHz,DMSO)δ8.43(dd,J＝8.1,2.3Hz,1H),8.06(dd,J＝7.6,0.9Hz,1H),7.89(d,J＝5.1Hz,1H),7.81(t,J＝5.6Hz,1H),7.49(t,J＝8.0Hz,1H),7.05(d,J＝8.3Hz,1H),6.56(d,J＝2.4Hz,1H),6.41(dd,J＝8.4,2.4Hz,1H),4.57(d,J＝5.5Hz,2H),3.82(s,3H),3.72(s,3H)。

¹⁹ F NMR(471MHz,DMSO)δ-149.9(s)

[M-H] ^- ＝389.2

Intermediate 30

4-bromo-2-chloro-1H-pyrrolo [2,3-b ] pyridine

1- (benzenesulfonyl) -4-bromopyrrolo [2,3-b ] pyridine

To a solution of 4-bromo-1H-pyrrolo [2,3-b ] pyridine (5.00 g,25.4 mmol) in DCM (130 mL) was added benzenesulfonyl chloride (4.86 mL,38.1 mmol), 4-dimethylaminopyridine (310 mg,2.54 mmol) and TEA (10.6 mL,76.13 mmol). The reaction mixture was stirred at room temperature for 2h. After completion, the reaction mixture was concentrated under reduced pressure. The crude product was suspended in DCM (50 mL) and concentrated onto silica gel. The material was purified by flash chromatography (silica gel, 0-50% EtOAc/petroleum ether) to give the product as a pale yellow solid (8.39 g, 98% yield).

[M+H] ⁺ ＝338.9

1- (benzenesulfonyl) -4-bromo-2-chloropyrrolo [2,3-b ] pyridine

Into a dry flask was charged 1- (benzenesulfonyl) -4-bromopyrrolo [2,3-b ]]Pyridine (3.50 g,10.4 mmol), sealed and with N ₂ (g) And (5) purging. THF (5) was added6 mL) and the mixture was cooled to-41 ℃. In N ₂ (g) Lithium diisopropylamide (2M in THF) (12.5 mL,24.9 mmol) was added slowly. The mixture was stirred at-41℃for 30min, after which benzenesulfonyl chloride (2.65 mL,20.8 mmol) was added. The reaction mixture was stirred at-41℃for 2.5h. The reaction mixture was quenched with water (35 mL) and diluted with EtOAc (70 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2X 20 mL). The organic layers were combined and washed with brine (10 mL), dried (MgSO ₄ ) Filtered and concentrated in vacuo. Flash chromatography (silica gel, 0-60% EtOAc/petroleum ether) afforded the product as a pale yellow solid (3.92 g, 71% yield).

[M+H] ⁺ ＝372.9

4-bromo-2-chloro-1H-pyrrolo [2,3-b ] pyridine

1- (benzenesulfonyl) -4-bromo-2-chloropyrrolo [2,3-b]Pyridine (3.92 g,7.38 mmol) was dissolved in 1, 4-dioxane (20 mL) and NaOtBu (1.66 g,14.8 mmol) was added. The reaction mixture was stirred at 80℃for 2h. The reaction mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The layers were separated and the organic layer was dried (MgSO ₄ ) Filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0-25% EtOAc/petroleum ether). Et for the product ₂ O was triturated, dissolved in EtOAc and concentrated in vacuo to give the product as a pale beige solid (1.03 g, 60%).

[M+H] ⁺ ＝232.9

¹ H NMR(CDCl ₃ ,400MHz)δ6.47(1H,s),7.32(1H,d,J＝5.3Hz),8.11(1H,d,J＝5.3Hz)。

Intermediate 31

N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

5-bromo-N- (2, 4-dimethoxybenzyl) isoquinoline1-amine (4.00 g,10.7 mmol), 2-trifluoroacetamide (1.82 g,16.1 mmol), copper (I) iodide (204 mg,1.07 mmol), K ₂ CO ₃ A mixture of (2.96 g,21.4 mmol) and DMF (189 mg, 241. Mu.L, 2.14 mmol) was dissolved in anhydrous 1, 4-dioxane (10.6 mL) and taken up in N ₂ The purge mixture was then heated to 75 ℃ and held for 24 hours. MeOH (30 mL) and water (30 mL) were added and the mixture was heated at 75 ℃ for 3.5h. The organic solvent was removed in vacuo and the residue partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2X 50 mL) and the combined organics were washed with brine (50 mL), dried (MgSO) ₄ ) Filtered and concentrated in vacuo. Flash chromatography (silica gel, 0-50% EtOAc/isohexane followed by 0-5% (0.7M NH) ₃ MeOH)/DCM) to give the product (1.74 g, 52%).

[M+H] ⁺ ＝310.2

¹ H NMR(d6DMSO,500MHz)δ3.71(3H,s),3.82(3H,s),4.58(2H,d,J＝5.7Hz),5.60(2H,s),6.39(1H,dd,J＝8.4,2.4Hz),6.55(1H,d,J＝2.4Hz),6.77(1H,dd,J＝7.6,0.9Hz),6.98-7.05(2H,m),7.17(1H,t,J＝7.9Hz),7.33(1H,t,J＝5.8Hz),7.42(1H,d,J＝8.3Hz),7.68(1H,d,J＝6.0Hz)。

Intermediate 32

8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine

3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (2.12 g,11.0 mmol) was dissolved in DCM (20 mL) followed by the addition of Boc ₂ O (3.61 g,16.5 mmol). The mixture was stirred for 18h. The mixture was concentrated under reduced pressure. Flash chromatography (silica gel, 0-70% EtOAc/isohexane) afforded the product as a white solid(2.66g，81％)。

[M+H] ⁺ ＝293.2

¹ H NMR(d6DMSO,500MHz)δ1.44(9H,s),3.83(2H,t,J＝5.5Hz),4.17(2H,t,J＝5.5Hz),4.77(2H,s)。

8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

3- (trifluoromethyl) -5, 6-dihydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine-7 (8H) -carboxylic acid tert-butyl ester (3.4 g,12 mmol) was dissolved in toluene (40 mL). Tetramethyl ethylenediamine (1.5 g,1.9mL,13 mmol) was added. In N ₂ (g) The reaction mixture was cooled to-78 ℃. Adding ⁿ BuLi (6.5 mL,2.5M in hexane, 16 mmol) and the mixture was stirred at-78℃for 10min. MeI (8.3 g,3.6ml,58 mmol) was added and the mixture stirred for a further 10min, after which time it was warmed to rt and stirred for 18h. The mixture was treated with NH ₄ Cl (aq) (20 mL) was diluted and extracted with EtOAc (3X 25 mL). The organic layers were combined, dried (MgSO ₄ ) Filtered and concentrated in vacuo. Flash chromatography (silica gel, 0-85% EtOAc/isohexane) afforded the product (2.2 g, 62%).

[M+H] ⁺ ＝307.2

8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine-7 (8H) -carboxylic acid tert-butyl ester (397 mg,1.30 mmol) was dissolved in DCM (9 mL). TFA (2 mL) was added. The mixture was stirred for 1.5h, after which it was concentrated under reduced pressure. The crude product was loaded onto SCX with MeOH, washed with MeOH and with 0.7M NH ₃ MeOH elution of (d). Concentration in vacuo afforded the product as a yellow oil (201 mg, 75%).

[M+H] ⁺ ＝207.2

¹ H NMR(CDCl3,500MHz)δ1.68(3H,d,J＝6.7Hz),3.22(1H,ddd,J＝13.6,10.3,4.6Hz),3.47(1H,ddd,J＝13.5,4.8,2.6Hz),4.04-4.18(2H,m),4.29(1H,q,J＝6.6Hz)。

Intermediate 33

(6- (3- (difluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methylamine

6- (3- (difluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) nicotinonitrile

With 3- (difluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]A solution of pyrazine (343 mg,1.97 mmol) and DIPEA (497 mg,3.84 mmol) in MeCN (3 mL) was treated with a solution of 2-fluoropyridine-5-carbonitrile (229 mg,1.88 mmol) in MeCN (3 mL). The mixture was heated at 85℃for 20h. After cooling, the solvent was removed in vacuo. Flash chromatography (silica gel, 0-3.5% (0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (366 mg, 70% yield).

[M+H] ⁺ ＝277.2

¹ H NMR(500MHz,DMSO-d6)4.17-4.29(4H,m),5.09(2H,s),7.18(1H,dd,J＝9.1,0.8Hz),7.37(1H,t,J＝51.8Hz),8.00(1H,dd,J＝9.0,2.3Hz),8.60(1H,dd,J＝2.4,0.7Hz)

According to general procedure 3a, 6- (3- (difluoromethyl) -5, 6-dihydro- [1,2, 4) is reduced using Raney nickel]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) nicotinonitrile (803 mg,1.31mmol) 4.5h. The solvent was removed in vacuo. Flash chromatography (silica gel, 0-14% (0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (217 mg, 58% yield).

[M+H] ⁺ ＝281.2

¹ H NMR(500MHz,DMSO-d6)1.75(2H,s),3.60(2H,s),4.06(2H,t,J＝5.5Hz),4.20(2H,t,J＝5.5Hz),4.92(2H,s),7.05(1H,d,J＝8.6Hz),7.35(1H,t,J＝51.9Hz),7.62(1H,dd,J＝8.7,2.4Hz),8.10(1H,d,J＝2.3Hz)

Specific embodiments of the invention

Example number 2185

N6- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

(6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Tert-butyl (6-bromoisoquinolin-1-yl) carbamate (130 mg,0.40 mmol) was reacted with (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (85 mg,0.36 mmol) using general method 4 and NaOtBu (80 mg,0.83 mmol) in THF (3 mL) at 60℃for 1h. The reaction mixture was quenched, concentrated and purified by flash chromatography (silica gel, 0-20% (containing 0.7 MNH) ₃ Purified with MeOH/DCM) to give the product as a colourless solid (170 mg, 93% yield).

[M+H] ⁺ ＝477.3

Using general procedure 7bBoc deprotection of tert-butyl (6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (155 mg,0.33 mmol). By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (82 mg, 66% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)δ1.43-1.53(2H,m),1.77-1.87(2H,m),1.94-2.02(2H,m),2.12(3H,s),2.55-2.61(2H,m),3.29-3.36(1H,m),4.35(2H,d,J＝5.9Hz),4.45(2H,s),6.28(2H,s),6.46(1H,d,J＝2.4Hz),6.52(1H,d,J＝5.8Hz),6.75(1H,t,J＝6.0Hz),6.87(1H,dd,J＝9.0,2.4Hz),7.25-7.30(2H,m),7.33-7.37(2H,m),7.53(1H,d,J＝5.8Hz),7.84(1H,d,J＝9.1Hz)

Example number 1003

N7- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) isoquinoline-1, 7-diamine

Following general method 4, 7-bromoisoquinolin-1-amine (51 mg,0.23 mmol) was reacted with (4- ((1-methylpiperidin-4-yl) oxy) phenyl) methylamine (50 mg,0.23 mmol) using anhydrous 1, 4-dioxane (3 mL) containing NaOtBu (2M in THF) (0.23 mL,0.46 mmol) at 50℃for 2h. The reaction was quenched, concentrated and purified by flash chromatography (silica gel, 0-20% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product, which was further purified by preparative HPLC (5-50% in basic mobile phase) to give the product as a pale brown solid (5 mg, 6% yield).

[M+H] ⁺ ＝363.2

¹ H NMR(500MHz,DMSO-d6)δ1.53-1.64(2H,m),1.86-1.94(2H,m),2.10-2.18(5H,m),2.56-2.62(2H,m),4.26-4.35(3H,m),6.26(2H,s),6.31(1H,t,J＝5.9Hz),6.71(1H,d,J＝5.7Hz),6.89-6.92(2H,m),7.01(1H,d,J＝2.2Hz),7.11(1H,dd,J＝8.8,2.2Hz),7.32-7.35(2H,m),7.40(1H,d,J＝8.8Hz),7.49(1H,d,J＝5.7Hz)。

Example No. 3253

N6- ((1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) methyl) isoquinoline-1, 6-diamine

4- ((4-cyano-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylic acid tert-butyl ester

Following general method 5b, tert-butyl 4- (bromomethyl) piperidine-1-carboxylate (1.20 g,4.30 mmol), 1H-pyrazole-4-carbonitrile (250 mg,2.69 mmol) and K were stirred in a microwave at 130℃C ₂ CO ₃ (921 mg,6.66 mmol) in NMP (5 mL) for 2h. The reaction was quenched with MeOH (5 mL) and diluted with water (50 mL). The product was extracted into TBME (2X 50 mL) and washed with brine (50 mL). The organic layer was dried (Na ₂ SO ₄ ) Filtration and concentration gave the product as a white solid (756 mg, 89% yield).

¹ H NMR(500MHz,DMSO-d6)δ1.00 -1.10(2H,m),1.39(9H,s),1.94 -2.05(1H,m),2.08 -2.21(2H,m),2.65-2.75(2H,m),3.91(2H,s),4.08(2H,d,J＝7.1Hz),8.07(1H,s),8.55(1H,s)。

1- (piperidin-4-ylmethyl) -1H-pyrazole-4-carbonitrile

Boc deprotection of tert-butyl 4- ((4-cyano-1H-pyrazol-1-yl) methyl) piperidine-1-carboxylate (900 mg,3.10 mmol) was carried out using general method 7b to give the product as a pale orange oil (517 mg, 76% yield).

[M+H] ⁺ ＝191.1

¹ H NMR (500 MHz, DMSO-d 6) delta 0.99-1.12 (2H, m), 1.30-1.40 (2H, m), 1.83-1.94 (1H, m), 2.34-2.44 (2H, m), 2.87-2.98 (2H, m), 4.04 (2H, d, J=7.2 Hz), 8.06 (1H, s), 8.55 (1H, s). No NH was observed.

1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazole-4-carbonitrile

/>

Following general method 9, 1- (piperidin-4-ylmethyl) -1H-pyrazole-4-carbonitrile (498 mg,2.62 mmol) was reacted with paraformaldehyde (314 mg,10.44 mmol) in DCM (6.5 mL) and DMF (0.5 mL) at 40℃for 5H. By flash chromatography (silica gel, 0-10% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product as a clear colorless oil (352 mg, 63% yield).

[M+H] ⁺ ＝205.3

¹ H NMR(500MHz,DMSO-d6)δ1.12 -1.26(2H,m),1.34 -1.45(2H,m),1.68 -1.82(3H,m),2.12(3H,s),2.68 -2.76(2H,m),4.06(2H,d,J＝7.2Hz),8.06(1H,s),8.55(1H,s)。

(1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) methylamine

Nitrile 1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazole-4-carbonitrile (200 mg,0.98 mmol) was reduced using Raney nickel CatCart for 4H according to general method 3 a. The crude residue was dissolved in MeOH, directly through SCX. The product was treated with 7M NH ₃ The solution in MeOH eluted (180 mg, 50% yield) and separated as a colorless oil.

[M+H] ⁺ ＝209.4

¹ H NMR(500MHz,DMSO-d6)δ1.10-1.23(2H,m),1.37-1.46(2H,m),1.62-1.71(1H,m),1.73-1.80(2H,m),2.11(3H,s),2.67-2.75(2H,m),3.56(2H,s),3.91(2H,d,J＝7.2,4.0Hz),7.32(1H,d,J＝2.7Hz),7.51(1H,s)。NH ₂ Hidden under the water peak.

Following general method 4, (1- ((1-methylpiperidin-4-yl) methyl) -1H-pyrazol-4-yl) methylamine (40 mg,0.19 mmol) was reacted with 6-bromoisoquinolin-1-amine (43 mg,0.19 mmol) at 50℃for 18H using anhydrous 1, 4-dioxane (3 mL) containing NaOtBu (37 mg,0.38 mmol). After elution via SCX, the crude product was further purified by preparative HPLC (10-40% in basic mobile phase) to give the product as a white solid (9.0 mg, 13% yield).

[M+H] ⁺ ＝351.4

¹ H NMR(500MHz,DMSO-d6)δ1.10-1.22(2H,m),1.37-1.44(2H,m),1.62-1.78(3H,m),2.11(3H,s),2.66-2.73(2H,m),3.93(2H,d,J＝7.2Hz),4.15(2H,d,J＝5.4Hz),6.28(2H,s),6.36(1H,t,J＝5.5Hz),6.54(1H,d,J＝2.3Hz),6.59(1H,d,J＝5.8Hz),6.86(1H,dd,J＝9.0,2.3Hz),7.42(1H,s),7.56(1H,d,J＝5.8Hz),7.66(1H,s),7.83(1H,d,J＝9.0Hz)。

Example number 3254

N6- ((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) isoquinoline-1, 6-diamine

(6- (((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general procedure 4, (1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methylamine (75 mg,0.34 mmol) was reacted with tert-butyl (6-bromoisoquinolin-1-yl) carbamate (120 mg,0.37 mmol) in the presence of NaOtBu (80 mg,0.83 mmol) in THF (3 mL) at 60℃for 1h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (121 mg, 69% yield).

[M+H] ⁺ ＝465.3

¹ H NMR(500MHz,DMSO-d6)1.18-1.43(3H,m),1.47(9H,s),1.64-1.77(2H,m),1.77-1.88(2H,m),2.66-2.82(6H,m),3.30-3.38(1H,m),4.11(2H,t,J＝7.1Hz),4.21(2H,d,J＝5.4Hz),6.70(1H,s),6.80-6.96(1H,m),6.95-7.12(1H,m),7.12-7.30(1H,m),7.46(1H,s),7.73(1H,s),7.75-8.01(2H,m).8.17-8.30(1H,m)

Tert-butyl (6- (((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (100 mg,0.22 mmol) was deprotected according to general procedure 7 b. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (35 mg, 43% yield).

[M+H] ⁺ ＝365.2

¹ H NMR(500MHz,DMSO-d6)1.04-1.18(2H,m),1.54-1.74(7H,m),2.09(3H,s),2.62-2.70(2H,m),4.07(2H,t,J＝7.2Hz),4.15(2H,d,J＝5.3Hz),6.28(2H,s),6.37(1H,t,J＝5.4Hz),6.54(1H,d,J＝2.3Hz),6.59(1H,d,J＝5.9Hz),6.86(1H,dd,J＝9.0,2.3Hz),7.42(1H,s),7.55(1H,d,J＝5.8Hz),7.69(1H,s),7.83(1H,d,J＝9.1Hz)

Example number 1004

3-chloro-N- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] pyridin-5-amine

Following general procedure 4, (4- ((1-methylpiperidin-4-yl) oxy) phenyl) methylamine (61 mg,0.28 mmol) was reacted with 5-bromo-3-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ]Pyridine (100 mg,0.28 mmol) was reacted at rt for 1h in the presence of THF (0.28 mL,0.56 mmol) containing 2M NaOtBu. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 1% nh) ₃ MeOH)/DCM) to give the product as a yellow oil (65 mg, 38% yield).

[M+H] ⁺ ＝501.2

¹ H NMR(500MHz,DMSO-d6)δ-0.10(9H,s),0.76-0.82(2H,m),1.55-1.65(2H,m),1.86-1.94(2H,m),2.13-2.24(5H,m),2.57-2.67(2H,m),3.42-3.53(2H,m),4.25(2H,d,J＝6.0Hz),4.27-4.36(1H,m),5.48(2H,s),6.20(1H,t,J＝6.0Hz),6.87-6.93(3H,m),7.28-7.31(2H,m),7.63(1H,s),7.94(1H,d,J＝2.6Hz)

3-chloro-N- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) -1H-pyrrolo [2,3-b ] pyridin-5-amine

3-chloro-N- (4- ((1-methylpiperidin-4-yl) oxy) benzyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrrolo [2,3-b ] cooled in an ice/water bath]To a solution of pyridin-5-amine (40 mg,0.08 mmol) in DCM (1 mL) was added dropwise TFA (0.10 mL,1.30 mmol) and the mixture was stirred for 1h. The reaction was warmed to rt and stirred for 18h. The reaction was diluted with MeOH (3 mL) and passed directly through SCX and washed with MeOH (30 mL). By using a catalyst containing 7M NH ₃ 50mL of MeOH) and concentrating. By flash chromatography (silica gel, 0-20% (containing 1% NH) ₃ MeOH)/DCM) and subsequently purified by preparative HPLC (5-50% MeCN/water, basic mobile phase) to afford the product as a pale yellow solid (7.0 mg, 23% yield).

[M+H] ⁺ ＝371.1

¹ H NMR(500MHz,DMSO-d6)δ1.57-1.67(2H,m),1.88-1.94(2H,m),2.15-2.24(5H,m),2.59-2.67(2H,m),4.23(2H,d,J＝6.0Hz),4.28-4.36(1H,m),6.06(1H,t,J＝6.0Hz),6.87(1H,d,J＝2.6Hz),6.89-6.93(2H,m),7.28-7.32(2H,m),7.41(1H,d,J＝2.8Hz),7.88(1H,d,J＝2.6Hz),11.44(1H,d,J＝1.8Hz)

Example No. 3255

N5- ((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) isoquinoline-1, 5-diamine

(5- (((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general method 4, (1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methylamine (75 mg,0.34 mmol) was reacted with tert-butyl (5-bromoisoquinolin-1-yl) carbamate (120 mg,0.37 mmol) in the presence of NaOtBu (80 mg,0.83 mmol) in THF (5 mL) at 60℃for 5H. After quenching the reaction mixture with AcOH (40. Mu.L, 0.70 mmol) for 5min, 1M NH was added ₃ Is added to the reaction mixture, the mixture is concentrated, and MeOH (20 mL) is added. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (35 mg, 22% yield).

[M+H] ⁺ ＝465.2

Using general procedure 7b, p- (5- (((1- (2- (1-methylpiperidin-4-yl) ethyl) -1H-pyrazol-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl esterDeprotection of butyl ester (35 mg,0.075 mmol). By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a red solid (5.0 mg, 17% yield).

[M+H] ⁺ ＝365.2

¹ H NMR(500MHz,DMSO-d6)δ1.04-1.21(3H,m),1.57-1.68(4H,m),1.81-1.94(2H,m),2.20(3H,s),2.74-2.81(2H,m),4.05(2H,t,J＝7.2Hz),4.26(2H,d,J＝5.6Hz),6.32(1H,t,J＝5.8Hz),6.49(2H,s),6.63(1H,d,J＝7.7Hz),7.12(1H,d,J＝6.1Hz),7.18(1H,t,J＝8.0Hz),7.32(1H,d,J＝8.3Hz),7.40(1H,d,J＝0.7Hz),7.64(1H,s),7.71(1H,d,J＝6.1Hz)

Example number 2186

N5- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 5-diamine

(5- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general procedure 4, (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (60 mg,0.26 mmol) was reacted with tert-butyl (5-bromoisoquinolin-1-yl) carbamate (90 mg,0.28 mmol) and NaOtBu (50 mg,0.52 mmol) in THF (3 mL) at 60℃for 3h. After quenching the reaction mixture and concentrating in vacuo, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (50 mg, 40% yield).

[M+H] ⁺ ＝477.3

According to general procedure 7b, tert-butyl (5- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (50 mg,0.10 mmol) is deprotected. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow solid (21 mg, 49% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)1.43-1.57(2H,m),1.79-1.89(2H,m),2.02-2.14(2H,m),2.17(3H,s),2.59-2.66(2H,m),3.37 -3.39(1H,m),4.44(2H,s),4.45(2H,s),6.43(1H,d,J＝7.7Hz),6.50(2H,s),6.76(1H,t,J＝6.0Hz),7.07-7.13(1H,m),7.21(1H,d,J＝6.1Hz),7.23-7.28(2H,m),7.30(1H,d,J＝8.3Hz),7.32-7.36(2H,m),7.75(1H,d,J＝6.1Hz)

Example number 2189

N6- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-3, 6-diamine

(6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-3-yl) carbamic acid tert-butyl ester

Following general procedure 4, tert-butyl (6-bromoisoquinolin-3-yl) carbamate (69 mg,0.21 mmol) is reacted with (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (50 mg,0.21 mmol) in THF (0.2 mg,0.4 mmol) containing 2M NaOtBu in THF (3 mL) at 60 ℃ for 1h. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (64 mg, 62% yield).

[M+H] ⁺ ＝477.3

Using general procedure 7b, tert-butyl (6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-3-yl) carbamate (64 mg,0.13 mmol) was deprotected. After elution via SCX, the crude product was purified by preparative HPLC (5-50% MeCN in water, basic mobile phase) to give the product as a pale pink solid (23 mg, 44% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)δ1.43-1.52(2H,m),1.80-1.86(2H,m),1.96-2.02(2H,m),2.12(3H,s),2.54-2.61(2H,m),3.34-3.37(1H,m),4.33(2H,d,J＝5.9Hz),4.45(2H,s),5.48(2H,s),6.17-6.23(2H,m),6.67(1H,dd,J＝8.9,2.2Hz),6.75(1H,t,J＝5.9Hz),7.28(2H,d,J＝8.1Hz),7.35(2H,d,J＝8.1Hz),7.44(1H,d,J＝8.9Hz),8.37(1H,s)。

Example number 2187

N6- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) quinoline-2, 6-diamine

Following general procedure 4, 6-bromoquinolin-2-amine (106 mg,0.47 mmol) was reacted with (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (111 mg,0.47 mmol) in the presence of THF (3 mL) containing 2m na otbu in THF (0.48 mg,0.96 mmol) at 60 ℃ for 2h. After elution via SCX, the crude product was purified by preparative HPLC (5-50% MeCN in water, basic mobile phase) to give the product as an off-white solid (11 mg, 6% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)δ1.44-1.52(2H,m),1.80-1.87(2H,m),1.95-2.02(2H,m),2.12(3H,s),2.55-2.62(2H,m),3.33-3.37(1H,m),4.30(2H,d,J＝6.0Hz),4.45(2H,s),5.35(2H,s),6.24(1H,t,J＝6.0Hz),6.50(1H,s),6.59(1H,d,J＝2.3Hz),7.09(1H,dd,J＝8.9,2.3Hz),7.28(2H,d,J＝8.0Hz),7.32(1H,d,J＝8.9Hz),7.37(2H,d,J＝8.0Hz),8.44(1H,s)。

Example number 2190

N6-methyl-N6- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

(6- (methyl (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general method 9, (6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester (95 mg,0.20 mmol) was reacted with DCM (3 mL) and DMF (0.3 mL) containing paraformaldehyde (24 mg,0.81 mmol) at 40℃for 3h. Diluting the reaction mixture with 0.7M NH ₃ In MeOH (10 mL) and concentrated under reduced pressure. By flash chromatography (silica gel, 0-15% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colourless gum (50 mg, 36% yield).

[M+H] ⁺ ＝491.5

Holding at rt using general procedure 7bTert-butyl (6- (methyl (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (46 mg,0.09 mmol) was deprotected for 48 h. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (15 mg, 39% yield).

[M+H] ⁺ ＝391.5

¹ H NMR(500MHz,DMSO-d6)δ1.42-1.53(2H,m),1.78-1.86(2H,m),1.95-2.05(2H,m),2.12(3H,s),2.53-2.62(2H,m),3.10(3H,s),3.29-3.33(1H,m),4.44(2H,s),4.70(2H,s),6.40(2H,s),6.63(1H,d,J＝5.9Hz),6.69(1H,d,J＝2.6Hz),7.04(1H,dd,J＝9.3,2.7Hz),7.16-7.21(2H,m),7.23-7.28(2H,m),7.57(1H,d,J＝5.9Hz),7.94(1H,d,J＝9.2Hz)。

Example number 2191

N6- (2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

(6- ((2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general procedure 4, (6-bromoisoquinolin-1-yl) carbamate (141 mg,0.44 mmol) was reacted with (2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (110 mg,0.44 mmol) and THF (3 mL) containing NaOtBu (84 mg,0.87 mmol) at 60 ℃ for 1h. After quenching, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (172 mg, 72% yield).

[M+H] ⁺ ＝495.5

Tert-butyl (6- ((2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (140 mg,0.25 mmol) was deprotected using general procedure 7 b. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (96 mg, 93% yield).

[M+H] ⁺ ＝395.4

¹ H NMR(500MHz,DMSO-d6)δ1.42-1.54(2H,m),1.79-1.87(2H,m),1.95-2.03(2H,m),2.12(3H,s),2.54-2.61(2H,m),3.34-3.37(1H,m),4.38(2H,d,J＝5.9Hz),4.47(2H,s),6.30(2H,s),6.47-6.50(1H,m),6.55(1H,d,J＝5.9Hz),6.67-6.72(1H,m),6.86-6.90(1H,m),7.10(1H,d,J＝7.9Hz),7.15(1H,d,J＝11.0Hz),7.34-7.39(1H,m),7.54(1H,d,J＝5.8Hz),7.86(1H,d,J＝9.0Hz)。

Example number 1005

N6- ((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

(6- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (75.0 mg,0.32 mmol) was reacted with tert-butyl (6-bromoisoquinolin-1-yl) carbamate (103 mg,0.32 mmol) in the presence of 1M KO ^t Bu was reacted in 1, 4-dioxane (0.64 mL,0.64 mmol) in the presence of 1, 4-dioxane (4 mL) at 60℃for 1h. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (104 mg, 49% yield).

[M+H] ⁺ ＝436.5

Methyl (6- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (90 mg,0.21 mmol) was deprotected using general procedure 14a for 4 h. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 2-20% (containing 0.7 MNH) ₃ MeOH)/DCM) was purified. The product was lyophilized to give the product as a white solid (49 mg, 60% yield).

[M+H] ⁺ ＝378.4

¹ H NMR(500MHz,DMSO-d6)δ1.19-1.34(2H,m),1.63-1.74(3H,m),1.83-1.92(2H,m),2.17(3H,s),2.74-2.82(2H,m),4.07(2H,d,J＝6.1Hz),4.29(2H,d,J＝5.8Hz),6.40(2H,s),6.54(1H,d,J＝2.4Hz),6.58(1H,d,J＝5.9Hz),6.68-6.74(1H,m),6.78(1H,d,J＝8.5Hz),6.87(1H,dd,J＝9.1,2.4Hz),7.54(1H,d,J＝5.9Hz),7.70(1H,dd,J＝8.5,2.5Hz),7.86(1H,d,J＝9.0Hz),8.17(1H,d,J＝2.4Hz)

Example number 1006

N6- ((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

Following general procedure 1b, (5, 6,78-tetrahydroimidazo [1,2-a]Pyridin-7-yl) methanol (890 mg,5.85 mmol) was reacted with 6-fluoronicotinonitrile (514 mg,5.85 mmol) for 5h. The crude reaction mixture was passed directly through SCX. Wash SCX with MeOH and with 7M NH ₃ The product was eluted with MeOH. By flash chromatography (silica gel, 0-10% (containing 0.7 NH) ₃ MeOH)/DCM) to give the product as a light brown solid (723 mg, 44% yield).

[M+H] ⁺ ＝255.3

(6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) carbamic acid tert-butyl ester

Following general procedure 3d, nitrile 6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a) is reduced in MeOH (14 mL) and THF (9.0 mL)]Pyridine-7-l) methoxy) nicotinonitrile (400 mg,1.57 mmol). After 18h, water (2 mL) was added and the reaction mixture was filtered, washed with THF (20 mL) and concentrated. By chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a viscous colorless gum (315 mg, 45% yield).

[M+H] ⁺ ＝359.4

Boc deprotection of tert-butyl ((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) carbamate (170 mg,0.47 mmol) was performed using general method 7 b. After elution via SCX, the product was isolated as a pale yellow oil (124 mg, 90% yield).

[M+H]+＝259.3

¹ H NMR (500 MHz, DMSO-d 6) 1.66-1.80 (1H, m), 2.08-2.18 (1H, m), 2.31-2.44 (1H, m), 2.47-2.50 (1H, m, obscured by DMSO), 2.93 (1H, ddd, J=16.3, 5.1,1.5 Hz), 3.76 (2H, s), 3.83-3.96 (1H, m), 4.03-4.14 (1H, m), 4.26 (2H, dd, J=6.6, 1.4 Hz), 6.81 (1H, d, J=1.3 Hz), 6.84 (1H, d, J=8.5 Hz), 6.99 (1H, d, J=1.2 Hz), 7.73 (1H, dd, J=8.5, 2.5 Hz), 8.11 (1H, d, J=2.4) (not observed to NH 2.4 Hz)

(6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-3-yl) methylamine (108 mg,0.42 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (118 mg,0.418 mmol) and THF (8 mL) containing NaOtBu (80 mg,0.83 mmol) at 60℃for 1h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (60 mg, 28% yield).

[M+H] ⁺ ＝459.4

Deprotection of methyl (6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (57 mg,0.12 mmol) was performed using general method 14a for 18h. After quenching, elution via SCX and lyophilization, the product was isolated as an off-white solid (45 mg, 89% yield).

[M+H] ⁺ ＝401.5

¹ H NMR (500 mhz, DMSO-d 6) δ1.67-1.78 (1H, m), 2.10-2.16 (1H, m), 2.31-2.41 (1H, m), 2.45-2.51 (1H, m, partially obscured by DMSO), 2.92 (1H, ddd, j=16.3, 5.0,1.5 Hz), 3.84-3.92 (1H, m), 4.05-4.11 (1H, m), 4.25 (2H, d, j=6.6 Hz), 4.31 (2H, d, j=5.8 Hz), 6.52-6.58 (3H, m), 6.61 (1H, d, j=6.0 Hz), 6.77-6.82 (2H, m), 6.84 (1H, d, j=8.5 Hz), 6.89 (1H, dd, j=9.1, 2.92 (1H, j=3.5 Hz), 4.05-4.11 (1H, m), 4.25 (2H, d, j=6.6 Hz), 4.31 (2H, j=5.8 Hz), 6.52-6.58 (3H, m), 6.61 (1H, d, j=6.0 Hz), 6.77-6.82 (2H, m), 6.84 (1H, j=8.5 Hz).

Examples 1023 and 1024 (enantiomers)

Following general procedure 4, (6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-3-yl) methylamine (108 mg,0.42 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (118 mg,0.418 mmol) and THF (8 mL) containing NaOtBu (80 mg,0.83 mmol) at 60℃for 1h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) was purified. The two enantiomers were separated chirally by reverse phase chiral Gilson prep (UV detection at 260nm, ambient column temperature, chiralPAK IC 20 x 250mm,5 μm column, flow rate 15mL/min, using 70% MeCN and 30% 0.1% aqueous ammonia) to give:

Enantiomer 1:

methyl (R) - (6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (61 mg,0.13mmol,26%, 99% purity), 1.03min, 99% purity (diode array).

The product was analyzed by analytical RP chiral HPLC (Agilent 1100HPLC,ChiralPAK IC 2.1X 150,3 μm column, flow rate 0.4mL/min, elution with 70/30MeCN/0.1% ammonia; 5.9min, purity 100% (UV at 240 nm))

[M+H] ⁺ ＝459.4

[M-H] ^- ＝457.3

Enantiomer 2:

(S) - (6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester (61 mg,0.13mmol,25%, purity 97%)

[M+H] ⁺ ＝459.4

[M-H] ^- =457.3, 1.03min, 97% purity (diode array).

The product was analyzed by analytical RP chiral HPLC (Agilent 1100HPLC,ChiralPAK IC 2.1X 150,3 μm column, flow rate 0.4mL/min, elution with 70/30MeCN/0.1% ammonia; 7.5min, purity 100% (UV at 240 nm)).

6-N- ({ 6- [ (7R) -5H,6H,7H, 8H-imidazo [1,2-a ] pyridin-7-ylmethoxy ] pyridin-3-yl } methyl) isoquinoline-1, 6-diamine (enantiomer 1, example No. 1023)

Deprotection of methyl (R) - (6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (60 mg,0.13 mmol) was carried out using general method 14a for 18 h. After quenching, elution via SCX and lyophilization, the product was isolated as a white solid (24 mg, 45% yield).

[M+H] ⁺ ＝401.2

¹ H NMR(500MHz,DMSO-d6)δ1.66-1.77(1H,m),2.09-2.16(1H,m),2.33-2.41(1H,m),2.45-2.50(1H,m),2.92(1H,dd,J＝16.4,5.0Hz),3.88(1H,td,J＝12.0,4.7Hz),4.04-4.11(1H,m),4.25(2H,d,J＝6.6Hz),4.30(2H,d,J＝5.7Hz),6.35(2H,s),6.54(1H,d,J＝2.3Hz),6.58(1H,d,J＝5.9Hz),6.70(1H,t,J＝5.8Hz),6.80(1H,s),6.84(1H,d,J＝8.5Hz),6.87(1H,dd,J＝9.0,2.3Hz),6.99(1H,s),7.55(1H,d,J＝5.8Hz),7.73(1H,dd,J＝8.5,2.5Hz),7.86(1H,d,J＝9.0Hz),8.20(1H,d,J＝2.4Hz)。

6-N- ({ 6- [ (7S+ -5H,6H,7H, 8H-imidazo [1,2-a ] pyridin-7-ylmethoxy ] pyridin-3-yl } methyl) isoquinoline-1, 6-diamine (enantiomer 2, example number 1024)

Deprotection of enantiomer 2 (S) - (6- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (60 mg,0.13 mmol) was performed using general method 14a for 18h. After quenching, elution via SCX and lyophilization, the product was isolated as an off-white solid (29 mg, 54% yield).

[M+H] ⁺ ＝401.2

¹ H NMR(500MHz,DMSO-d6)δ1.66-1.77(1H,m),2.09-2.16(1H,m),2.32-2.42(1H,m),2.45-2.49(1H,m),2.92(1H,dd,J＝16.2,5.0Hz),3.88(1H,td,J＝11.9,4.7Hz),4.03-4.11(1H,m),4.25(2H,d,J＝6.6Hz),4.30(2H,d,J＝5.7Hz),6.33(2H,s),6.54(1H,d,J＝2.3Hz),6.57(1H,d,J＝5.9Hz),6.69(1H,t,J＝5.8Hz),6.80(1H,d,J＝1.2Hz),6.84(1H,d,J＝8.5Hz),6.87(1H,dd,J＝9.0,2.3Hz),6.99(1H,s),7.55(1H,d,J＝5.8Hz),7.73(1H,dd,J＝8.5,2.5Hz),7.85(1H,d,J＝9.0Hz),8.19(1H,d,J＝2.4Hz)

Example number 2192

N6- (2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

4- ((4-bromo-3-chlorophenyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

Using general procedure 1a, 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (706 mg,3.52 mmol) was reacted with 1-bromo-4- (bromomethyl) -2-chlorobenzene (1.00 g,3.52 mmol). The crude product was purified by flash chromatography (silica gel, 0-100% EtOAc/isohexane) to give the product as a colorless solid (990 mg, 68% yield).

[M-tBu+H] ⁺ ＝347.8

¹ H NMR(500MHz,DMSO-d6)δ1.35-1.44(11H,m),1.79-1.86(2H,m),2.98-3.09(2H,m),3.56(1H,tt,J＝8.1,3.7Hz),3.59-3.67(2H,m),4.51(2H,s),7.25(1H,dd,J＝8.2,2.0Hz),7.57(1H,d,J＝2.0Hz),7.74(1H,d,J＝8.2Hz)。

4- ((4-bromo-3-chlorophenyl) oxy) -1-methylpiperidine

Tert-butyl 4- ((4-bromo-3-chlorobenzyl) oxy) piperidine-1-carboxylate (990 mg,2.45 mmol) was reacted for 2h using general method 10. The reaction mixture was concentrated, then dissolved in EtOAc (50 mL) with 2M Na ₂ CO ₃ (50 mL) and brine (30 mL). The organic phase was dried (MgSO ₄ ) Filtration and concentration gave the product as a colourless oil (780 mg, 95% yield).

[M+H] ⁺ ＝318.0

¹ H NMR(500MHz,DMSO-d6)δ1.46-1.58(2H,m),1.80-1.88(2H,m),1.96-2.05(2H,m),2.14(3H,s),2.55-2.62(2H,m),3.36(1H,tt,J＝8.5,4.0Hz),4.48(2H,s),7.24(1H,dd,J＝8.2,2.0Hz),7.56(1H,d,J＝2.0Hz),7.74(1H,d,J＝8.2Hz)。

2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile

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Using general procedure 2, 4- ((4-bromo-3-chlorophenyl) oxy) -1-methylpiperidine (400 mg,1.26 mmol) was reacted at 80℃for 16h and concentrated. By flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (203 mg, 83% yield).

[M+H] ⁺ ＝256.1

¹ H NMR(500MHz,DMSO-d6)δ1.47-1.59(2H,m),1.82-1.91(2H,m),1.96-2.07(2H,m),2.14(3H,s),2.56-2.63(2H,m),3.39(1H,tt,J＝8.5,4.1Hz),4.60(2H,s),7.48-7.51(1H,m),7.67(1H,d,J＝1.4Hz),7.96(1H,d,J＝8.0Hz)

(2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

Following general procedure 3b, nitrile 2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzonitrile (185 mg,0.70 mmol) was reduced for 16 h. The product was isolated as a yellow gum (162 mg, 82% yield).

[M+H] ⁺ ＝269.0

(6- ((2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Using general procedure 4, (2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (100 mg,0.37 mmol) was reacted with tert-butyl (6-bromoisoquinolin-1-yl) carbamate (120 mg,0.37 mmol) in a solution containing 1M KO ^t Bu was reacted at 60℃for 8h in the presence of THF (4 mL) in THF (0.74 mL,0.74 mmol). After quenching the reaction, it was purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (38 mg, 19% yield).

[M+H] ⁺ ＝511.2

Tert-butyl (6- ((2-chloro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (38 mg,0.074 mmol) was deprotected using general procedure 7 b. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) was purified. The product was lyophilized to give the product as a white solid (12 mg, 38% yield).

[M+H] ⁺ ＝411.2

¹ H NMR(500MHz,DMSO-d6)δ1.44-1.53(2H,m),1.79-1.86(2H,m),1.95-2.02(2H,m),2.12(3H,s),2.54-2.61(2H,m),3.32-3.38(1H,m),4.41(2H,d,J＝5.9Hz),4.47(2H,s),6.30(2H,s),6.41(1H,d,J＝2.3Hz),6.54(1H,d,J＝5.8Hz),6.78(1H,t,J＝6.0Hz),6.89(1H,dd,J＝9.0,2.4Hz),7.23(1H,dd,J＝8.0,1.7Hz),7.38(1H,d,J＝7.9Hz),7.42(1H,d,J＝1.6Hz),7.54(1H,d,J＝5.9Hz),7.87(1H,d,J＝9.0Hz)。

Example number 2177

N6- (4- (2- (1-methylpiperidin-4-yl) ethyl) benzyl) isoquinoline-1, 6-diamine

4- ((4-cyanophenyl) ethynyl) piperidine-1-carboxylic acid tert-butyl ester

By N ₂ Purging 4-bromobenzonitrile (1.04 g,5.73 mmol), tert-butyl 4-ethynyl piperidine-1-carboxylate (1.00 g,4.78 mmol) and copper (I) iodide (46 mg,0.24 mmol) in NEt ₃ Suspension in (10 mL)The solution was then added with Pd (PPh ₃ ) ₄ (552 mg,0.48 mmol) and with N ₂ The mixture was again purged for 30min. The reaction was heated to 90 ℃ and stirred for 16h. The reaction was cooled and water (30 mL) was added, after which the aqueous layer was extracted with EtOAc (3×30 mL). The combined organics were dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-100% etoac/isohexane) to give the product as an orange solid (1.59 g, 96% yield).

[M-tBu+H] ⁺ ＝255.1

¹ H NMR(500MHz,DMSO-d6)δ1.40(9H,s),1.48-1.57(2H,m),1.78-1.86(2H,m),2.87-2.94(1H,m),3.09-3.20(2H,m),3.61-3.67(2H,m),7.55-7.61(2H,m),7.79-7.85(2H,m)ppm。

4- ((1-methylpiperidin-4-yl) ethynyl) benzonitrile

Following general method 10, tert-butyl 4- ((4-cyanophenyl) ethynyl) piperidine-1-carboxylate (1.00 g,3.22 mmol) was reacted for 2h. The reaction mixture was concentrated, then dissolved in EtOAc (50 mL) with 2M Na ₂ CO ₃ (50 mL) and brine (3X 30 mL). The organic phase was dried (MgSO ₄ ) Filtration and concentration gave the product as an off-white solid (451 mg, 59% yield).

[M+H] ⁺ ＝225.1

¹ H NMR(500MHz,DMSO-d6)δ1.57-1.70(2H,m),1.82-1.91(2H,m),2.12-2.25(5H,m),2.60-2.72(3H,m),7.54-7.59(2H,m),7.80-7.84(2H,m)ppm。

4- (2- (1-methylpiperidin-4-yl) ethyl) benzonitrile

To a solution of 4- ((1-methylpiperidin-4-yl) ethynyl) benzonitrile (100 mg,0.45 mmol) in EtOH (5 mL) was added 10% Pd/C (50 mg,0.05 mmol) and at high pressure on steelIn the kettle at H ₂ (3 bar) for 16h. Crude reactant viaFiltration and washing with EtOH (10 mL) followed by concentration in vacuo afforded the product as a white solid (99 mg, 92% yield).

[M+H] ⁺ ＝229.2

¹ H NMR(500MHz,DMSO-d6)δ1.12-1.20(3H,m),1.46-1.53(2H,m),1.60-1.69(2H,m),1.76-1.82(2H,m),2.13(3H,s),2.64-2.70(2H,m),2.71-2.77(2H,m),7.40-7.44(2H,m),7.72-7.75(2H,m)ppm。

(4- (2- (1-methylpiperidin-4-yl) ethyl) phenyl) methylamine

Following general method 3b, nitrile 4- (2- (1-methylpiperidin-4-yl) ethyl) benzonitrile (165 mg,0.72 mmol) was reduced for 16h. The product was isolated as a yellow gum (175 mg, 89% yield) and used without further purification.

[M+H] ⁺ ＝233.2

¹ H NMR(500MHz,DMSO-d6)δ1.10-1.19(3H,m),1.44-1.51(2H,m),1.60-1.67(2H,m),1.73-1.79(2H,m),1.85-2.04(2H,m),2.11(3H,s),2.53-2.58(2H,m),2.68-2.74(2H,m),3.66(2H,s),7.08-7.12(2H,m),7.19-7.23(2H,m)ppm。

(6- ((4- (2- (1-methylpiperidin-4-yl) ethyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general procedure 4, (4- (2- (1-methylpiperidin-4-yl) ethyl) phenyl) methylamine (85 mg,0.37 mmol) was reacted with tert-butyl (6-bromoisoquinolin-1-yl) carbamate (124 mg,0.38 mmol) in the presence of 2M KO ^t Bu was reacted at 60℃for 1h in the presence of THF (4 mL) in THF (0.37 mL,0.73 mmol). After elution via SCX, the purified product was purified by flash chromatography (silicaGlue 0-20% (containing 0.7M NH) ₃ The crude product was purified with MeOH/DCM to give the product (62 mg, 32% yield).

[M+H] ⁺ ＝475.3

N6- (4- (2- (1-methylpiperidin-4-yl) ethyl) benzyl) isoquinoline-1, 6-diamine dihydrochloride

Following general method 7b, tert-butyl (6- ((4- (2- (1-methylpiperidin-4-yl) ethyl) benzyl) amino) isoquinolin-1-yl) carbamate (62 mg,0.13 mmol) is deprotected. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (35 mg, 57% yield).

[M+H] ⁺ ＝375.3

¹ H NMR (500 mhz, dmso-d 6) delta 1.35-1.45 (3H, m), 1.45-1.53 (2H, m), 1.78-1.87 (2H, m), 2.55-2.61 (5H, m), 2.61-2.70 (2H, m), 3.15-3.22 (2H, m), 4.38 (2H, d, j=5.9 Hz), 6.67 (1H, d, j=2.3 Hz), 6.74 (1H, d, j=6.8 Hz), 7.03 (1H, dd, j=9.2, 2.3 Hz), 7.18 (2H, m), 7.30 (2H, m), 7.44-7.49 (2H, m), 7.88 (2H, s), 8.11 (1H, d, j=9.2), 11.34 (1H, s) ppm. No 1 x exchangeable protons were observed.

Example number 2193

N- (4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinolin-6-amine

Following general procedure 4, (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (50 mg,0.21 mmol) was reacted with 6-bromoisoquinoline (44 mg,0.21 mmol) in the presence of 1, 4-dioxane (5 mL) containing NaOtBu (41 mg,0.43 mmol) at 90 ℃ for 18h. After quenching the reaction mixture, the crude product was purified by preparative HPLC and lyophilized (Waters, base (0.1% ammonium bicarbonate), basic, waters x-Bridge Prep-C18,5 μm,19 x 50mm column, 10-40% MeCN/water) to give the product as a colorless solid (14 mg, 18% yield).

[M+H] ⁺ ＝362.5

¹ H NMR(500MHz,DMSO-d6)δ1.40-1.57(2H,m),1.77-1.87(2H,m),1.91-2.05(2H,m),2.12(3H,s),2.54-2.62(2H,m),3.34-3.37(1H,m),4.39(2H,d,J＝5.9Hz),4.46(2H,s),6.61(1H,d,J＝2.2Hz),7.11(1H,t,J＝5.9Hz),7.14(1H,dd,J＝8.9,2.3Hz),7.26-7.32(2H,m),7.34(1H,d,J＝5.8Hz),7.35-7.40(2H,m),7.75(1H,d,J＝8.9Hz),8.15(1H,d,J＝5.8Hz),8.85(1H,s)ppm。

Example number 2194

N6- (4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

4- ((4-Cyanobenzyl) oxy) -3, 3-difluoropiperidine-1-carboxylic acid tert-butyl ester

Using general procedure 1a, 3-difluoro-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (500 mg,2.11 mmol) was reacted with 4- (bromomethyl) benzonitrile (413 mg,2.11 mmol). The crude product was purified by flash chromatography (silica gel, 0-50% EtOAc/isohexane) to give the product as a thick colorless oil (490 mg, 63% yield).

[M-boc+H] ⁺ ＝253.3

¹ H NMR(500MHz,DMSO-d6)1.40(9H,s),1.67-1.78(1H,m),1.85-1.95(1H,m),3.47-3.56(1H,m),3.55-3.65(1H,m),3.73-3.86(1H,m),3.88-4.00(1H,m),4.70-4.85(2H,m),7.50-7.59(2H,m),7.80-7.87(2H,m)。CH ₂ Is shielded by water.

4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) benzonitrile

Following general method 10, tert-butyl 4- ((4-cyanobenzyl) oxy) -3, 3-difluoropiperidine-1-carboxylate (400 mg,1.14 mmol) was reacted for 18h. By flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a thick colorless oil (211 mg, 67% yield).

[M+H] ⁺ ＝267.3

¹ H NMR(500MHz,DMSO-d6)1.69-1.79(1H,m),1.86-1.96(1H,m),2.22(3H,s),2.24(1H,s),2.73-2.84(1H,m),3.71-3.81(1H,m),4.69-4.83(2H,m),7.50-7.58(2H,m),7.80-7.87(2H,m)。CH ₂ Is masked by DMSO.

(4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine

Nitrile 4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) benzonitrile (200 mg,0.75 mmol) was reduced following general method 3 b. The product was isolated as a colourless solid (200 mg, 94% yield) and was used without further purification.

[M+H] ⁺ ＝271.4

¹ H NMR(500MHz,DMSO-d6)δ1.31-1.39(2H,m),1.67-1.89(4H,m),2.20(3H,s),2.22-2.26(1H,m),2.67-2.80(1H,m),3.60-3.66(1H,m),3.70(2H,s),4.61(2H,s),7.25-7.29(2H,m),7.29-7.33(2H,m)。

(6- ((4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Using general procedure 4, (4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (197mg, 0.73 mmol) was reacted with tert-butyl (6-bromoisoquinolin-1-yl) carbamate (236 mg,0.73 mmol) and THF (3 mL) containing NaOtBu (140 mg,1.46 mmol) at 60℃for 1h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (212 mg, 54% yield).

[M+H] ⁺ ＝513.5

Tert-butyl (6- ((4- (((3, 3-difluoro-1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (42 mg,0.082 mmol) was deprotected using general procedure 7 b. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (26 mg, 75% yield).

[M+H] ⁺ ＝413.2

¹ H NMR (500 mhz, DMSO-d 6) delta 1.66-1.77 (1H, m), 1.80-1.89 (1H, m), 2.16-2.24 (4H, m), 2.42-2.51 (2H, m), 2.68-2.80 (1H, m), 3.62-3.71 (1H, m), 4.36 (2H, d, j=5.6 Hz), 4.61 (2H, s), 6.32 (2H, d, j=6.7 Hz), 6.47 (1H, d, j=2.3 Hz), 6.53 (1H, d, j=5.9 Hz), 6.78 (1H, t, j=6.0 Hz), 6.88 (1H, dd, j=9.0, 2.3 Hz), 7.27-7.32 (2H, m), 7.35-7.39 (2H, m), 7.53 (1H, j=6.7 Hz), 6.47 (1H, d, j=2.3 Hz), and the signal is masked by DMSO (1H, d=5.3 Hz).

Example number 1008

N- ((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) isoquinolin-6-amine

Following general method 4, (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (40 mg,0.17 mmol) was reacted with 6-bromoisoquinoline (40 mg,0.19 mmol) and NaOtBu (35 mg,0.36 mmol) in THF (4 mL) at 60℃for 1h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (39 mg, 62% yield).

[M+H] ⁺ ＝363.2

¹ H NMR(500MHz,DMSO-d6)1.22-1.31(2H,m),1.64-1.72(3H,m),1.81-1.90(2H,m),2.16(3H,s),2.74-2.81(2H,m),4.08(2H,d,J＝6.1Hz),4.33(2H,d,J＝5.6Hz),6.68(1H,d,J＝2.3Hz),6.79(1H,d,J＝8.5Hz),7.02(1H,t,J＝5.7Hz),7.11(1H,dd,J＝8.9,2.3Hz),7.38(1H,d,J＝5.8Hz),7.72(1H,dd,J＝8.5,2.5Hz),7.75(1H,d,J＝8.9Hz),8.18(1H,d,J＝5.8Hz),8.20(1H,d,J＝2.5Hz),8.86(1H,s)。

Example number 1009

N5- ((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

(5- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

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Using general procedure 4, (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (58 mg,0.25 mmol) was reacted with tert-butyl (5-bromoisoquinolin-1-yl) carbamate (80 mg,0.25 mmol) and with NaOtBu (50 mg,0.52 mmol) of THF (6 mL) was reacted at 60℃for 1h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (59 mg, 49% yield).

[M+H] ⁺ ＝478.3

Tert-butyl (5- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (59 mg,0.12 mmol) was deprotected using general method 7 b. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (35 mg, 74% yield).

[M+H] ⁺ ＝378.2

¹ H NMR(500MHz,DMSO-d6)1.21-1.32(2H,m),1.64-1.73(3H,m),1.81-1.94(2H,m),2.17(3H,s),2.74-2.82(2H,m),4.06(2H,d,J＝6.1Hz),4.38(2H,d,J＝5.7Hz),6.50(2H,s),6.54(1H,d,J＝7.7Hz),6.65(1H,t,J＝5.9Hz),6.74(1H,d,J＝8.5Hz),7.12-7.18(2H,m),7.32(1H,d,J＝8.3Hz),7.69(1H,dd,J＝8.5,2.5Hz),7.74(1H,d,J＝6.1Hz),8.16(1H,d,J＝2.4Hz)

Example number 1011

6- ((4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) oxy) isoquinolin-1-amine

T-butyl ((4- (chloromethyl) benzyl) oxy) dimethylsilane

In an ice/water bathTert-butylchlorodimethylsilane (529 mg,3.51 mmol) was added to a solution of (4- (chloromethyl) phenyl) methanol (500 mg,3.19 mmol) and imidazole (283 mg,4.15 mmol) in DCM (5 mL) while cooling. The reaction was warmed to rt and stirred for 1h. By KHSO ₄ (aqueous) (10 mL) the reaction was quenched and the layers separated. The organic layer was dried (Na ₂ SO ₄ ) Filtration and concentration gave the product (861 mg, 95% yield) as a clear colorless liquid, which was used without further purification.

¹ H NMR(500MHz,DMSO-d6)0.08(6H,s),0.91(9H,s),4.72(2H,s),4.75(2H,s),7.29-7.33(2H,m),7.39-7.42(2H,m)。

4- ((4- (((tert-Butyldimethylsilyl) oxy) methyl) benzyl) oxy) piperidine-1-carboxylic acid tert-butyl ester

Following general method 5a, tert-butyl 4-hydroxypiperidine-1-carboxylate (639 mg,3.17 mmol) was reacted with tert-butyl ((4- (chloromethyl) benzyl) oxy) dimethylsilane (860 mg,3.17 mmol) for 20h. The crude product was purified by flash chromatography (silica gel, 0-100% EtOAc/isohexane) to give the product as a colorless oil (466 mg, 28% yield).

[M-boc+H] ⁺ ＝336.2

¹ H NMR(500MHz,DMSO-d6)0.08(6H,s),0.90(9H,s),1.35-1.43(11H,m),1.77-1.86(2H,m),3.01 -3.08(2H,m),3.51-3.57(1H,m),3.59-3.66(2H,m),4.50(2H,s),4.70(2H,s),7.26-7.31(4H,m)。

4- ((4- (((tert-butyldimethylsilyloxy) methyl) benzyl) oxy) -1-methylpiperidine

Using general procedure 10, tert-butyl 4- ((4- (((tert-butyldimethylsilyl) oxy) methyl) benzyl) oxy) piperidine-1-carboxylate (460 mg,1.06 mmol) was reacted for 3h. The reaction mixture is reactedCooled to rt, taken up with Na ₂ CO ₃ (saturated aqueous, 30 mL) and extracted with EtOAc (3X 20 mL). The organic phase was dried (MgSO ₄ ) Filtration and concentration gave the product as a yellow oil (238 mg, 25% yield). The crude product was used in the next step without further purification.

[M+MeCN] ⁺ ＝392.2

4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methanol

TBAF (1M in THF) (2 mL,2 mmol) was added to a solution of 4- ((4- (((tert-butyldimethylsilyl) oxy) methyl) benzyl) oxy) -1-methylpiperidine (238 mg,0.68 mmol) in THF (5 mL) and stirred at rt for 18h. The reaction was diluted with water (5 mL) and concentrated. The crude mixture was dissolved in 1:1DCM/MeOH, filtered and concentrated. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a clear colorless oil (108 mg, 55% yield).

[M+H] ⁺ ＝236.1

¹ H NMR (500 MHz, meOH-d 4) 1.64-1.77 (2H, m), 1.89-2.02 (2H, m), 2.23-2.33 (5H, m), 2.71-2.80 (2H, m), 3.46-3.55 (1H, m), 4.55 (2H, s), 4.61 (2H, s), 7.34 (4H, s). 1 x exchangeable protons.

Using general method 1c, (4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methanol (98 mg,0.36 mmol) was reacted with 6-bromoisoquinolin-1-amine (80 mg,0.36 mmol) for 4h. The product was purified by preparative HPLC (mass orientation 5-50% in alkaline mobile phase) and lyophilized (Waters, base (0.1% ammonium bicarbonate), alkaline, waters X-Bridge Prep-C18,5 μm, 19X 50mm column, 5-50% MeCN/water) to give the product as an off-white solid (4 mg, 3% yield).

[M+H]＝378.2

¹ H NMR(500MHz,DMSO-d6)1.44-1.55(2H,m),1.81-1.89(2H,m),1.96-2.04(2H,m),2.13(3H,s),2.57-2.62(2H,m),3.33-3.38(1H,m),4.50(2H,s),5.21(2H,s),6.61(2H,s),6.80(1H,d,J＝5.8Hz),7.12(1H,dd,J＝9.1,2.6Hz),7.19(1H,d,J＝2.6Hz),7.34-7.38(2H,m),7.44-7.49(2H,m),7.72(1H,d,J＝5.8Hz),8.10(1H,d,J＝9.1Hz)。

Example number 1012

N6- ((6- ((1-isopropylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

6- ((1-isopropylpiperidin-4-yl) methoxy) nicotinonitrile

Using general procedure 1b, (1-isopropylpiperidin-4-yl) methanol (300 mg,1.91 mmol) was reacted with 6-fluoronicotinonitrile (233 mg,1.91 mmol) at rt for 18h. The reaction mixture was diluted with MeCN (20 mL) and passed throughAnd (5) filtering the pad. The filtrate was concentrated and purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow solid (225 mg, 44% yield).

[M+H] ⁺ ＝260.3

¹ H NMR(500MHz,DMSO-d6)0.96(6H,d,J＝6.9Hz),1.20-1.32(2H,m),1.65-1.78(2H,m),2.06-2.18(2H,m),2.62-2.73(1H,m),2.75 -2.86(2H,m),3.26-3.31(1H,m),4.18(2H,d,J＝6.2Hz),7.00(1H,d,J＝8.7Hz),8.08-8.20(1H,m),8.62-8.72(1H,m)。

(6- ((1-isopropylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine

Nitrile 6- ((1-isopropylpiperidin-4-yl) methoxy) nicotinonitrile (215 mg,0.83 mmol) was reduced using a Raney nickel cartridge for 90min according to general method 3 a. The resulting solution was concentrated to give the product as a colorless solid (215 mg, 96% yield).

[M+H] ⁺ ＝264.4

¹ H NMR (500 mhz, dmso-d 6) 0.95 (6H, d, j=6.6 Hz), 1.14-1.28 (2H, m), 1.68-1.74 (2H, m), 2.02-2.14 (2H, m), 2.62-2.71 (1H, m), 2.73-2.83 (2H, m), 2.81-3.05 (1H, m), 3.67 (2H, s), 4.06 (2H, d, j=6.1 Hz), 6.75 (1H, d, j=8.5 Hz), 7.67 (1H, dd, j=8.5, 2.5 Hz), 8.05 (1H, d, j=2.4 Hz). NH was not observed

(6- (((6- ((1-isopropylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Using general procedure 4, tert-butyl (6-bromoisoquinolin-1-yl) carbamate (123 mg,0.38 mmol) was reacted with (6- ((1-isopropylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (100 mg,0.38 mmol) and NaOtBu (73 mg,0.76 mmol) in THF (6 mL) at 60℃for 1h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (137 mg, 68% yield).

[M+H] ⁺ ＝506.5

Using general procedure 7b, p- (6- (((6- ((1-isopropylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino)) Tert-butyl isoquinolin-1-yl) carbamate (133 mg,0.26 mmol) was deprotected. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (63 mg, 58% yield).

[M+H] ⁺ ＝406.2

¹ H NMR(500MHz,DMSO-d6)0.95(6H,d,J＝6.5Hz),1.15-1.28(2H,m),1.59-1.75(3H,m),2.02-2.13(2H,m),2.61-2.70(1H,m),2.72-2.81(2H,m),4.06(2H,d,J＝6.1Hz),4.28(2H,d,J＝5.4Hz),6.26-6.32(2H,m),6.53(1H,d,J＝2.3Hz),6.57(1H,d,J＝5.9Hz),6.67(1H,t,J＝5.9Hz),6.78(1H,d,J＝8.5Hz),6.84-6.88(1H,m),7.55(1H,d,J＝5.8Hz),7.66-7.73(1H,m),7.85(1H,d,J＝9.1Hz),8.17(1H,d,J＝2.4Hz)。

Example number 2210

N- (1-aminoisoquinolin-6-yl) -4- (((1-methylpiperidin-4-yl) oxy) methyl) benzenesulfonamide

4- ((4-Bromobenzyloxy) piperidine-1-carboxylic acid tert-butyl ester

Using general procedure 5a, tert-butyl 4-hydroxypiperidine-1-carboxylate (1.00 g,4.97 mmol) was reacted with 1-bromo-4- (bromomethyl) benzene (1.24 g,4.97 mmol) for 16h. Saturated NaHCO ₃ (30 mL) was added to the reaction mixture and the product was extracted into TBME (2X 50 mL). The combined organic layers were dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-50% etoac/isohexane) to give the product as a colorless solid (1.44 g, 75% yield).

[M-boc] ⁺ ＝270.2/271.9

¹ H NMR(500MHz DMSO-d 6)1.34-1.45(11H,m),1.76-1.86(2H,m),2.98-3.10(2H,m),3.52-3.58(1H,m),3.58-3.66(2H,m),4.50(2H,s),7.27-7.32(2H,m),7.51-7.55(2H,m)。

4- ((4-bromophenylmethyl) oxy) -1-methylpiperidine

Using general procedure 10, tert-butyl 4- ((4-bromobenzyl) oxy) piperidine-1-carboxylate (1.85 g,5.00 mmol) was reacted for 16h. After elution via SCX, the product was isolated as a clear orange liquid (1.31 g, 88% yield).

[M+H] ⁺ ＝284.2/286.2

¹ H NMR(500MHz,DMSO-d 6)1.43-1.58(2H,m),1.76-1.88(2H,m),1.93-2.04(2H,m),2.13(3H,s),2.54-2.67(2H,m),3.33-3.39(1H,m),4.47(2H,s),7.22-7.32(2H,m),7.48-7.58(2H,m)

4- (((1-methylpiperidin-4-yl) oxy) methyl) benzenesulfonamide

A mixture of 4- ((4-bromophenylmethyl) oxy) -1-methylpiperidine (1.30 g,4.57 mmol) in THF (6 mL) was cooled in a dry ice/acetone bath and added dropwise ⁿ BuLi (2.5M in hexane) (1.83 mL,4.57 mmol) and the reaction was stirred for 1h while continuing to cool in a dry ice/acetone bath. Sulfuryl chloride (371 μl,4.57 mmol) was added dropwise and the reaction mixture was stirred in a dry ice/acetone bath for 15min. NH is added to ₃ (0.5M in 1, 4-dioxane) (27 mL,13.7 mmol) was added dropwise to the solution followed by warming to rt and stirring for 2h. 1M HCl (aqueous) (18 mL,18.3 mmol) was added and the suspension concentrated. Dissolving the mixture in saturated K ₂ CO ₃ (aqueous) (60 mL) and extracted into EtOAc (6X 60 mL). The combined organic layers were dried (Na ₂ SO ₄ ) Filtering and concentrating. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (272 mg, 20% yield).

[M+H] ⁺ ＝285.3

¹ H NMR(500MHz,DMSO-d 6)1.46-1.57(2H,m),1.82-1.89(2H,m),1.96-2.04(2H,m),2.13(3H,s),2.54-2.63(2H,m),3.34-3.41(1H,m),4.57(2H,s),7.33(2H,s),7.43-7.57(2H,m),7.75-7.85(2H,m)。

Following general procedure 4, [ tBuXPhos Pd (allyl) was used]OTf (15 mg,0.02 mmol) as ligand tert-butyl (6-bromoisoquinolin-1-yl) carbamate (68 mg,0.21 mmol) was reacted with 4- (((1-methylpiperidin-4-yl) oxy) methyl) benzenesulfonamide (60 mg,0.21 mmol) and DMF containing NaOtBu (41 mg,0.43 mmol) at 40℃for 18h. The reaction was stirred at 80℃for 12h to cleave the boc protecting group. After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to give the product as an off-white solid (20 mg, 8% yield).

[M+H] ⁺ ＝427.4

¹ H NMR(500MHz,DMSO-d6)1.40-1.55(2H,m),1.76-1.88(2H,m),1.96-2.06(2H,m),2.14(3H,s),2.55-2.63(2H,m),3.25-3.42(1H,m),4.51(2H,s),6.69(2H,s),6.72(1H,d,J＝5.9Hz),7.16(1H,dd,J＝8.9,2.2Hz),7.27(1H,d,J＝2.2Hz),7.43-7.50(2H,m),7.67(1H,d,J＝5.8Hz),7.74-7.82(2H,m),8.01(1H,d,J＝9.1Hz),10.60(1H,br.s)。

Example number 2197

N5- (2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) isoquinoline-1, 5-diamine

(5- ((2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) phenyl) methylamine (150 mg,0.59 mmol) was reacted with (5-bromoisoquinolin-1-yl) carbamate (121 mg,0.43 mmol) and NaOtBu (83.0 mg,0.86 mmol) in THF (6 mL) at 60℃for 1h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (45 mg, 21% yield).

[M+H] ⁺ ＝453.5

¹ H NMR(500MHz,DMSO-d6)δ1.44-1.54(2H,m),1.79-1.85(2H,m),1.95-2.03(2H,m),2.12(3H,s),2.55-2.60(3H,m),3.66(3H,s),4.46(2H,s),4.53(2H,d,J＝5.3Hz),6.56(1H,d,J＝7.6Hz),7.06(2H,d,J＝8.1Hz),7.15(1H,d,J＝11.1Hz),7.25-7.28(1H,m),7.30-7.34(2H,m),7.99(1H,d,J＝6.1Hz),8.23(1H,d,J＝5.9Hz),9.86(1H,s)ppm。

Deprotection of methyl (5- ((2-fluoro-4- (((1-methylpiperidin-4-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (42 mg,0.093 mmol) was accomplished using general method 14a over 2 h. After quenching and elution via SCX, the product was lyophilized to give the product as an off-white solid (31 mg, 83% yield).

[M+H] ⁺ ＝395.4

¹ H NMR(500MHz,DMSO-d6)δ1.43-1.55(2H,m),1.78-1.87(2H,m),1.94-2.02(2H,m),2.12(3H,s),2.55-2.60(2H,m),3.32-3.38(1H,m),4.46(2H,s),4.48(2H,d,J＝5.8Hz),6.44(1H,d,J＝7.7Hz),6.51(2H,s),6.69(1H,t,J＝5.9Hz),7.04-7.07(1H,m),7.12-7.16(2H,m),7.20(1H,d,J＝6.1Hz),7.27-7.31(1H,m),7.33(1H,d,J＝8.3Hz),7.75(1H,d,J＝6.1Hz)ppm。

Example No. 4260

N5- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine

Using general procedure 1b, tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (353 mg,1.64 mmol) was reacted with 2-fluoroisonicotinic nitrile (200 mg,1.64 mmol) for 18h. The reaction mixture was cooled to rt and diluted with water (10 mL). The crude product was extracted into DCM (2X 25 mL) and dried (MgSO ₄ ) Filtering and concentrating. The residue was purified by flash chromatography (silica gel, 5-100% EtOAc/petroleum ether) to give the product as a pale yellow oil (500 mg,1.58mmol, 96% yield).

[M-boc+H] ⁺ ＝218.1

According to general procedure 3a, nitrile 4- (((4-cyanopyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (500 mg,1.58 mmol) was reduced using Raney nickel for 2 h. The solvent was removed in vacuo to give the product as a colourless oil (497 mg, 98% yield).

[M+H] ⁺ ＝322.1

¹ H NMR(CDCl ₃ 400MHz)δ1.25(2H,qd,J＝12.4,4.4Hz),1.46(9H,s),1.73-1.83(2H,m),1.89-2.00(1H,m),2.33(2H,br s),2.73(2H,t,J＝12.8Hz),3.86(2H,s),4.04-4.19(4H,m),6.65-6.75(1H,m),6.77-6.88(1H,m),8.07(1H,dd,J＝5.3,0.7Hz)ppm

4- (((4- (((1- ((2, 4-dimethoxybenzyl) amino) isoquinolin-5-yl) amino) methyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

Following general procedure 4, tert-butyl 4- (((4- (aminomethyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (497 mg,1.55 mmol) was reacted with 5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine (635 mg,1.7 mmol) and Cs-containing ₂ CO ₃ (1014 mg,3.09 mmol) of 1, 4-dioxane (6 mL) was reacted at 60℃for 18h. The reaction was cooled to rt and AcOH (177 μl,3.09 mmol) was added. The reaction mixture is passed throughFiltered, washed with EtOAc (50 mL) and concentrated. The residue was purified by flash chromatography (silica gel, 10-100% EtOAc/petroleum ether) to give the product as a pale yellow gum (800 mg, 84% yield).

[M+H] ⁺ ＝614.3

¹ H NMR(400MHz,CDCl ₃ )δ0.83-0.97(2H,m),1.45(9H,s),1.59(3H,s),1.77-1.99(3H,m),2.72(2H,t,J＝12.3Hz),3.80(3H,s),3.86(3H,s),4.47(2H,d,J＝5.5Hz),4.72-4.78(3H,m),5.63(1H,t,J＝5.3Hz),6.44-6.55(3H,m),6.75(1H,s),6.85-6.90(2H,m),7.08(1H,d,J＝8.4Hz),7.20-7.32(3H,m),8.05(1H,d,J＝6.1Hz),8.09(1H,d,J＝5.4Hz)ppm

N1- (2, 4-Dimethoxybenzyl) -N5- ((2- (piperidin-4-ylmethoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine

Following general procedure 7a, tert-butyl 4- (((4- (((1- ((2, 4-dimethoxybenzyl) amino) isoquinolin-5-yl) amino) methyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (800 mg,1.3 mmol) was deprotected for 25 h. The reaction mixture was concentrated, converted to free base using bicarbonate cartridge and purified with Et ₂ O (20 mL) was triturated to give the product as an orange oil (708 mg, 97% yield).

[M+H] ⁺ ＝514.2

N1- (2, 4-Dimethoxybenzyl) -N5- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine

Following general method 9, N1- (2, 4-dimethoxybenzyl) -N5- ((2- (piperidin-4-ylmethoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine (1530 mg,0.30 mmol) was reacted with formaldehyde (37% in water) (153 μl,1.49 mmol). By flash chromatography (silica gel, 0-100% (2% NH) ₃ The crude product was purified in EtOAc/MeCN/EtOH (3:3:1)/petroleum ether to give the product as a pale yellow gum (95 mg, 54% yield).

¹ H NMR(CDCl ₃ ,400MHz)δ1.35-1.45(2H,m),1.70-1.77(1H,m),1.79-1.87(2H,m),1.94(2H,td,J＝11.8,2.5Hz),2.27(3H,s),2.86(2H,d,J＝11.6Hz),3.81(3H,s),3.86(3H,s),4.12(2H,d,J＝6.4Hz),4.46(2H,d,J＝5.6Hz),4.74(3H,t,J＝6.1Hz),5.63(1H,t,J＝5.3Hz),6.45(1H,dd,J＝8.2,2.4Hz),6.50(1H,d,J＝2.4Hz),6.55(1H,d,J＝7.7Hz),6.75(1H,dd,J＝1.5,0.8Hz),6.84-6.87(1H,m),6.88(1H,dd,J＝5.3,1.5Hz),7.08(1H,d,J＝8.4Hz),7.22(1H,t,J＝8.0Hz),7.31(1H,dd,J＝8.2,3.9Hz),8.04(1H,d,J＝6.1Hz),8.09(1H,dd,J＝5.3,0.7Hz)ppm。

Deprotection of N1- (2, 4-dimethoxybenzyl) -N5- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine (95 mg,0.18 mmol) was carried out at rt for 1h according to general method 12. The product was purified by automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (39 mg, 57% yield).

[M+H] ⁺ ＝378.2

¹ H NMR(DMSO,400MHz)δ1.16-1.29(2H,m),1.57-1.70(3H,m),1.80(2H,td,J＝11.6,2.3Hz),2.12(3H,s),2.72(2H,dt,J＝11.7,3.2Hz),4.04(2H,d,J＝6.1Hz),4.43(2H,d,J＝6.0Hz),6.37(1H,d,J＝7.6Hz),6.51(2H,s),6.71(1H,d,J＝1.4Hz),6.79(1H,t,J＝6.1Hz),6.95(1H,dd,J＝5.3,1.4Hz),7.11(1H,t,J＝8.0Hz),7.17-7.21(1H,m),7.33(1H,d,J＝8.3Hz),7.76(1H,d,J＝6.1Hz),8.03(1H,dd,J＝5.3,0.6Hz)ppm。

Example No. 4261

N6- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

(6- (((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (6-bromoisoquinolin-1-yl) carbamate (119 mg,0.435 mmol) was reacted with (2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methylamine (100 mg,0.43 mmol) and THF (6 mL) containing NaOtBu (82.0 mg,0.85 mmol) at 60℃for 1h. After quenching, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (134 mg, 69% yield).

[M+H] ⁺ ＝436.4

Methyl (6- (((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (105 mg,0.22 mmol) was deprotected using general procedure 14a over 2 h. After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to give the product as a colorless solid (55 mg, 66% yield).

[M+H] ⁺ ＝378.5

¹ H NMR(500MHz,DMSO-d6)δ1.17-1.30(2H,m),1.60-1.70(3H,m),1.77-1.86(2H,m),2.13(3H,s),2.70-2.78(2H,m),4.06(2H,d,J＝6.1Hz),4.37(2H,d,J＝6.2Hz),6.31(2H,s),6.42(1H,d,J＝2.3Hz),6.53(1H,d,J＝5.9Hz),6.75(1H,s),6.83(1H,t,J＝6.2Hz),6.85-6.90(1H,m),6.94-6.99(1H,m),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.1Hz),8.06(1H,d,J＝5.3Hz)。

Example number 1017

1- (4- (((5- (((1-aminoisoquinolin-6-yl) amino) methyl) pyridin-2-yl) oxy) methyl) piperidin-1-yl) -2-methylpropan-2-ol

4- (((5-bromopyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid benzyl ester

Benzyl 4- (hydroxymethyl) piperidine-1-carboxylate (1.00 g,4.01 mmol) was reacted with 5-bromo-2-fluoropyridine (413 μl,4.01 mmol) using general method 1 a. The crude product was purified by flash chromatography (silica gel, 0-30% EtOAc/isohexane) to give the product as a colourless gum (1.22 g, 71% yield) which was allowed to stand.

[M+H] ⁺ ＝405.0

¹ H NMR(500MHz,DMSO-d 6)1.11-1.22(2H,m),1.74(2H,d,J＝13.0Hz),1.99(2H,s),2.72-2.93(2H,m),3.99-4.07(1H,m),4.10(2H,d,J＝6.5Hz),5.07(2H,s),6.80-6.84(1H,m),7.28-7.41(5H,m),7.89(1H,dd,J＝8.8,2.6Hz),8.24-8.28(1H,m)

4- (((5-formylpyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid benzyl ester

Benzyl 4- (((5-bromopyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (400 mg,0.99 mmol), et was sealed under a CO atmosphere (1.5 bar) ₃ N (0.41 mL,2.96 mmol), triethylsilane (0.47 mL,2.96 mmol), and PdCl ₂ (dppf)-CH ₂ Cl ₂ A solution of the adduct (80 mg,0.10 mmol) in DMF (6 mL) was heated at 90℃for 4h before cooling. The reaction mixture was dissolved in EtOAc (40 mL) and then washed with 1M HCl (aqueous) (40 mL), water/brine (1:1, 40 mL) and brine (40 mL). The organic phase was dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by chromatography (silica gel, 0-40% EtOAc/isohexane) to give the product as a colourless gum (282 mg, 79% yield) which was allowed to stand.

[M+H] ⁺ ＝355.1

¹ H NMR(500MHz,DMSO-d6)1.15-1.26(2H,m),1.71-1.81(2H,m),1.95-2.07(1H,m),2.73-2.95(2H,m),4.02-4.09(2H,m),4.26(2H,d,J＝6.5Hz),5.08(2H,s),6.99(1H,d,J＝8.6Hz),7.30-7.40(5H,m),8.12(1H,dd,J＝8.6,2.4Hz),8.75(1H,d,J＝2.3Hz),9.96(1H,s)

4- (((5- (((1- (bis (t-butoxycarbonyl) amino) isoquinolin-6-yl) amino) methyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid benzyl ester

A solution of benzyl 4- (((5-formylpyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (150 mg,0.42 mmol), tert-butyl (6-aminoisoquinolin-1-yl) (tert-butoxycarbonyl) carbamate (150 mg,0.42 mmol) and AcOH (23.9. Mu.L, 0.42 mmol) in MeOH (5 mL) was treated with sodium cyanoborohydride (30 mg,0.48 mmol) and then heated to 70℃for 3h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL) and taken up with NaHCO ₃ (20 mL), water (20 mL) and brine (20 mL), followed by drying (MgSO) ₄ ) Filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, 0-100% EtOAc/isohexane) to give the product as a yellow foam (132 mg, 45% yield).

[M+H] ⁺ ＝698.4

¹ H NMR(500MHz,DMSO-d 6)1.10-1.22(2H,m),1.31(18H,s),1.67-1.79(2H,m),1.89-1.99(1H,m),2.70-2.93(2H,m),3.99-4.06(2H,m),4.09(2H,d,J＝6.5Hz),4.33(2H,d,J＝5.4Hz),5.07(2H,s),6.77(1H,d,J＝2.3Hz),6.80(1H,d,J＝8.5Hz),7.11-7.16(2H,m),7.29-7.39(5H,m),7.43(1H,d,J＝5.8Hz),7.50(1H,d,J＝9.1Hz),7.73(1H,dd,J＝8.5,2.4Hz),8.07(1H,d,J＝5.8Hz),8.20(1H,d,J＝2.4Hz)。

(tert-Butoxycarbonyl) (6- (((6- (piperidin-4-ylmethoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Benzyl 4- (((5- (((1- (bis (t-butoxycarbonyl) amino) isoquinolin-6-yl) amino) methyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (122 mg,0.18 mmol) in MeOH (4 mL) was treated with 10% Pd/C (19 mg,0.02 mmol) and dissolved in H ₂ Sealing under atmosphere (2.5 bar). The reaction was heated at 50℃for 2h (4 bar). The reaction mixture is passed throughFiltered and concentrated. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ The crude product was purified with MeOH/DCM) to give the product as a colorless solid (65 mg, yield)Rate 65%).

[M+H] ⁺ ＝564.3

¹ H NMR (500 mhz, dmso-d 6) 1.12-1.23 (2H, m), 1.31 (18H, s) 1.65-1.71 (2H, m), 1.79-1.88 (1H, m), 2.51-2.55 (2H, m), 2.95-3.01 (2H, m), 4.07 (2H, d, j=6.6 Hz), 4.34 (2H, d, j=5.5 Hz), 6.76-6.80 (2H, m), 7.12 (1H, t, j=5.8 Hz), 7.14-7.17 (1H, m), 7.43 (1H, d, j=5.8 Hz), 7.51 (1H, d, j=9.2 Hz), 7.72 (1H, dd, j=8.8, 2.5 Hz), 8.07 (1H, d, j=5.8 Hz), 8.20 (1H, t, j=5.8 Hz), and no observation of NH.

(tert-Butoxycarbonyl) (6- (((6- ((1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

To tert-butyl (tert-butoxycarbonyl) (6- (((6- (piperidin-4-ylmethoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (45 mg,0.08 mmol) and K ₂ CO ₃ (22 mg,0.16 mmol) to a stirred suspension of 2, 2-dimethyloxirane (203 mg,2.76 mmol) in DMF (1 mL) and the reaction heated at 40℃for 4 days. The reaction mixture was diluted with EtOAc (30 mL) and taken up in saturated Na ₂ CO ₃ (aqueous solution) (20 mL), brine/water (1:1) (20 mL) and brine (20 mL), followed by drying (MgSO) ₄ ) Filtered and concentrated in vacuo. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colourless glass (21 mg, 39% yield).

[M+H] ⁺ ＝636.6

Using general procedure 7b, p- (tert-butoxycarbonyl) (6- (((6- ((1- (2-hydroxy-2-methylpropyl) piperidin-4-yl)) piperidin-4-yl)) Methoxy) pyridin-3-yl methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester (21 mg,0.033 mmol) deprotection. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) and lyophilizing the product to afford the product as a colorless solid (13 mg, 89% yield).

[M+H] ⁺ ＝436.2

¹ H NMR(500MHz,DMSO-d6)δ1.07(6H,s),1.22-1.34(2H,m),1.60-1.70(3H,m),2.05-2.13(2H,m),2.17(2H,s),2.89-2.96(2H,m),4.01(1H,s),4.07(2H,d,J＝6.1Hz),4.29(2H,d,J＝5.8Hz),6.36(2H,s),6.54(1H,d,J＝2.3Hz),6.58(1H,d,J＝6.1Hz),6.70(1H,t,J＝5.9Hz),6.75-6.80(1H,m),6.87(1H,dd,J＝9.0,2.3Hz),7.55(1H,d,J＝5.9Hz),7.70(1H,dd,J＝8.5,2.5Hz),7.86(1H,d,J＝9.0Hz),8.17(1H,d,J＝2.5Hz)。

Example number 1018

6- (2- (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) ethyl) isoquinolin-1-amine

5-ethynyl-2- ((1-methylpiperidin-4-yl) methoxy) pyridine

Following general method 1b, 5-ethynyl-2-fluoropyridine (281mg, 2.32 mmol) was reacted with (1-methylpiperidin-4-yl) methanol (300 mg,2.32 mmol) at rt for 18h. The reaction mixture is passed throughFiltered, eluted with EtOAc, and concentrated. By flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (266 mg, 49% yield).

[M+H]+＝231.1

¹ H NMR(500MHz,DMSO-d6)1.22-1.33(2H,m),1.65-1.73(3H,m),1.79-1.88(2H,m),2.14(3H,s),2.73-2.79(2H,m),4.12(2H,d,J＝6.2Hz),4.24(1H,s),6.83(1H,dd,J＝8.6,0.8Hz),7.78(1H,dd,J＝8.6,2.4Hz),8.29(1H,d,J＝2.2Hz)。

6- ((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) ethynyl) isoquinolin-1-amine

With three vacuum N ₂ (g) Periodically a solution of 5-ethynyl-2- ((1-methylpiperidin-4-yl) methoxy) pyridine (125 mg,0.54 mmol), 6-bromoisoquinolin-1-amine (145 mg,0.65 mmol) and copper (I) iodide (6 mg, 0.003mmol) in DMF (5 mL) was degassed before nitrogen was bubbled through for 10min. Pd (PPh) was added ₃ ) ₄ (63 mg,0.06 mmol) and with three vacuum N ₂ (g) The solution was again degassed and replaced with N ₂ (g) And then the cleaning is carried out for 10min. The reaction was heated to 80 ℃ and stirred for 65h. The reaction was cooled to rt and water (2 mL) and DCM (5 mL) were added. The crude reaction mixture was loaded onto SCX in MeOH. Wash SCX with MeOH (30 mL) and with 7M NH ₃ The product was eluted with MeOH (50 mL). The resulting mixture was concentrated. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an orange solid (136 mg, 63% yield).

[M+H] ⁺ ＝373.2

¹ H NMR(500MHz,DMSO-d6)1.22-1.36(2H,m),1.66-1.78(3H,m),1.83-1.92(2H,m),2.17(3H,s),2.75-2.83(2H,m),4.16(2H,d,J＝6.1Hz),6.87(2H,s),6.92(2H,d,J＝5.8Hz),7.55(1H,dd,J＝8.6,1.7Hz),7.84(1H,d,J＝5.8Hz),7.88-7.94(2H,m),8.22(1H,d,J＝8.6Hz),8.43(1H,d,J＝2.4Hz)。

To 6- ((6- ((1-methylpiperidin-4-yl) methoxy)Yl) pyridin-3-yl) ethynyl) isoquinolin-1-amine (135 mg,0.36 mmol) in EtOH (5 mL) was added 10% Pd/C (60 mg,0.06 mmol) and at rt in a steel autoclave at H ₂ (1 bar) the reaction was stirred for 3h. Crude reactant viaFiltered and washed with EtOH (10 mL) before being concentrated in vacuo. By chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (58 mg, 41% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)1.20-1.33(2H,m),1.62-1.74(3H,m),1.86-1.95(2H,m),2.18(3H,s),2.76-2.82(2H,m),2.88-2.94(2H,m),2.95-3.02(2H,m),4.04(2H,d,J＝6.1Hz),6.65-6.72(3H,m),6.80(1H,d,J＝5.8Hz),7.34(1H,dd,J＝8.5,1.8Hz),7.46(1H,d,J＝1.8Hz),7.57(1H,dd,J＝8.5,2.5Hz),7.74(1H,d,J＝5.8Hz),7.94(1H,d,J＝2.5Hz),8.09(1H,d,J＝8.5Hz)。

Examples numbers 2198 and 2199

N6- (2-fluoro-4- ((((4S, 5R) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine and N6- (2-fluoro-4- (((4R, 5R) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine

5- ((4-bromo-3-fluorobenzyl) oxy) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester

Following general method 5a, 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (800 mg,3.75 mmol) was reacted with 1-bromo-4- (bromomethyl) -2-fluorobenzene (1.00 g,3.75 mmol) at rt for 16h. The crude product was purified by flash chromatography (silica gel, 0-50% EtOAc/isohexane) to give the product as a thick colorless oil (805 mg, 47% yield).

[M- ^t Bu+H] ⁺ ＝344.0/346.0

¹ H NMR(500MHz,DMSO-d6)1.34-1.41(9H,m),1.43-1.54(2H,m),1.60-1.66(1H,m),1.85-1.93(1H,m),2.62-2.67(1H,m),2.70-2.78(1H,m),3.06-3.16(1H,m),3.69-3.74(1H,m),4.02-4.08(1H,m),4.42-4.52(2H,m),7.13(1H,dd,J＝8.2,1.9Hz),7.31(1H,dd,J＝9.9,1.9Hz),7.64-7.70(1H,m).F NMR(471MHz,DMSO-d6)-108.60

5- ((4-bromo-3-fluorobenzyl) oxy) -2-methyl-2-azabicyclo [2.2.1] heptane

Using general procedure 10, 5- ((4-bromo-3-fluorobenzyl) oxy) -2-azabicyclo [2.2.1]Tert-butyl heptane-2-carboxylate (800 mg,2.00 mmol) was reacted for 3h. After cooling to rt, the reaction was taken up in saturated Na ₂ CO ₃ (aqueous) (50 mL) and extracted with EtOAc (3X 30 mL). The organic phase was dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-50% etoac/isohexane) to give the product as an off-white solid (428 mg, 65% yield). [ M+H ]] ⁺ ＝314.0/316.0

¹ H NMR(500MHz,DMSO-d 6)1.21-1.29(1H,m),1.45-1.52(2H,m),1.79(1H,d,J＝9.5Hz),2.01-2.09(1H,m),2.13(3H,s),2.40-2.45(1H,m),2.62(1H,dd,J＝9.5,4.4Hz),3.00-3.05(1H,m),3.48-3.54(1H,m),4.50-4.40(2H,m),7.12(1H,dd,J＝8.2,1.9Hz),7.30(1H,dd,J＝9.9,1.9Hz),7.64 -7.70(1H,m)。

¹⁹ F NMR(471MHz,DMSO-d 6)-108.66。

2-fluoro-4- (((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzonitrile

Use general purpose medicineUsing method 2, 5- ((4-bromo-3-fluorobenzyl) oxy) -2-methyl-2-azabicyclo [2.2.1]Heptane (480 mg,1.53 mmol) was reacted for 88h and concentrated. By chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless oil (177 mg, 29% yield).

[M+H] ⁺ ＝261.1

¹ H NMR(500MHz,DMSO-d 6)1.23-1.31(1H,m),1.46-1.55(2H,m),1.79(1H,d,J＝9.5Hz),2.07(1H,dd,J＝13.6,6.9Hz),2.13(3H,s),2.42-2.47(1H,m),2.62(1H,dd,J＝9.6,4.5Hz),3.01-3.05(1H,m),3.54(1H,d,J＝6.9Hz),4.52-4.62(2H,m),7.34-7.37(1H,m),7.41-7.46(1H,m),7.88-7.93(1H,m)。

¹⁹ F NMR(471MHz,DMSO)δ-108.79。

(2-fluoro-4- (((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) phenyl) methylamine

Nitrile 2-fluoro-4- (((2-methyl-2-azabicyclo [ 2.2.1) using a Raney nickel cartridge) using general method 3a over 1h]Hept-5-yl) oxy) methyl benzonitrile (50 mg,0.19 mmol). The resulting solution was concentrated to give the product as a pale brown oil (45 mg, 75% yield). [ M+H ] ] ⁺ ＝265.1

¹ H NMR (500 MHz, DMSO-d 6) 1.21-1.28 (1H, m), 1.45-1.53 (2H, m), 1.80 (1H, d, J=9.6 Hz), 2.01-2.09 (1H, m), 2.14 (3H, s), 2.42-2.46 (1H, m), 2.63 (1H, dd, J=9.6, 4.4 Hz), 3.01-3.06 (1H, m), 3.50 (1H, dd, J=6.9, 2.4 Hz), 3.73 (2H, s), 4.35-4.50 (2H, m), 7.05 (1H, dd, J=11.1, 1.6 Hz), 7.10 (1H, dd, J=7.7, 1.6 Hz), 7.41-7.47 (1H, m). 2 x exchangeable protons.

¹⁹ F NMR(471MHz,DMSO-d 6)-120.50。

(6- ((2-fluoro-4- ((((4R, 5S) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

And

(6- ((2-fluoro-4- ((((4S, 5S) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (2-fluoro-4- (((2-methyl-2-azabicyclo [2.2.1 ])]Hept-5-yl) oxy) methyl phenyl methylamine (45 mg,0.17 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (48 mg,0.17 mmol) and THF (3 mL) containing NaOtBu (2M in THF) (0.17 mL,0.34 mmol) at 60℃for 2h. After quenching and elution via SCX, the sample was purified by flash chromatography on silica gel (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to separate the two individual diastereomers:

methyl (6- ((2-fluoro-4- ((((4R, 5S) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (13 mg, 16% yield) was isolated as a clear colorless oil.

[M+H] ⁺ ＝465.2

Methyl (6- ((2-fluoro-4- ((((4S, 5S) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate (20 mg, 24% yield) was isolated as a clear colorless oil.

[M+H] ⁺ ＝465.2

The stereochemistry, relative and absolute configuration are arbitrarily assigned to the two diastereomers, unknown.

N6- (2-fluoro-4- ((((4R. Times., 5S. Times.) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine (example No. 2199)

Following general method 14a, methyl (13 mg,0.03 mmol) of (6- ((2-fluoro-4- ((((4R, 5S) -2-methyl-2-azabicyclo [2.2.1] hept-5-l) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate is deprotected over 20 h. After quenching, elution via SCX and lyophilization, the product was obtained as a colorless solid (10 mg, 84% yield). Arbitrarily assigning stereochemistry; the relative and absolute configurations are unknown.

[M+H] ⁺ ＝407.5

¹ H NMR(500MHz,DMSO-d 6)1.23-1.31(1H,m),1.47-1.54(2H,m),1.81-1.89(1H,m),2.02-2.09(1H,m),2.17(3H,s),2.43-2.46(1H,m),2.60-2.69(1H,m),3.04-3.11(1H,m),3.49-3.54(1H,m),4.38(2H,d,J＝5.7Hz),4.39-4.48(2H,m),6.32(2H,s),6.48(1H,d,J＝2.4Hz),6.55(1H,d,J＝5.9Hz),6.72(1H,t,J＝6.0Hz),6.88(1H,dd,J＝9.1,2.4Hz),7.09(1H,dd,J＝7.9,1.6Hz),7.14(1H,dd,J＝11.1,1.6Hz),7.34-7.39(1H,m),7.54(1H,d,J＝5.8Hz),7.86(1H,d,J＝9.1Hz)。

F NMR(471MHz,DMSO-d 6)-119.12。

N6- (2-fluoro-4- ((((4R. Times., 5R. Times.) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) isoquinoline-1, 6-diamine (example No. 2199)

Deprotection of methyl KOH (20 mg,0.43 mmol) of (6- ((2-fluoro-4- ((((4R. 5R. X) -2-methyl-2-azabicyclo [2.2.1] hept-5-yl) oxy) methyl) benzyl) amino) isoquinolin-1-yl) carbamate was carried out using general method 14a for 20 h. After elution through SCX, the product was isolated to give the product as a colourless solid (18 mg, 98% yield). Arbitrarily assigning stereochemistry; the relative and absolute configurations are unknown.

[M+H] ⁺ ＝407.5

¹ H NMR(500MHz,DMSO-d6)1.21-1.27(1H,m),1.45-1.53(2H,m),1.78-1.84(1H,m),2.01-2.08(1H,m),2.15(3H,s),2.42-2.47(1H,m),2.62(1H,s),3.02-3.07(1H,m),3.47-3.53(1H,m),4.38(2H,d,J＝5.8Hz),4.39-4.48(2H,m),6.31(2H,s),6.48(1H,d,J＝2.3Hz),6.55(1H,d,J＝5.8Hz),6.71(1H,t,J＝6.0Hz),6.88(1H,dd,J＝9.0,2.4Hz),7.09(1H,dd,J＝7.8,1.6Hz),7.13(1H,dd,J＝11.1,1.6Hz),7.34-7.39(1H,m),7.54(1H,d,J＝5.8Hz),7.86(1H,d,J＝9.0Hz)。

F NMR(471MHz,DMSO-d6)-119.13。

Example number 4408

N6- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

(6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (2- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-4-yl) methylamine (75 mg,0.29 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (90 mg,0.32 mmol) and THF (5 mL) containing NaOtBu (56 mg,0.58 mmol) at 60℃for 3h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (90 mg, 66% yield).

[M-H] ^- ＝457.2

Deprotection of methyl (6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (50 mg,0.11 mmol) was performed using general method 14a for 3h. After quenching, elution via SCX and lyophilization, the product was isolated as an off-white solid (34 mg, 76% yield).

[M+H] ⁺ ＝401.2

¹ H NMR(DMSO-d6,400MHz)δ1.63-1.77(1H,m),2.06-2.15(1H,m),2.29-2.41(1H,m),2.43-2.49(1H,m),2.84-2.96(1H,m),3.79-3.92(1H,m),4.01-4.11(1H,m),4.24(2H,d,J＝6.6Hz),4.39(2H,d,J＝6.1Hz),6.31(2H,s),6.44(1H,d,J＝2.3Hz),6.53(1H,d,J＝5.9Hz),6.78-6.82(2H,m),6.85(1H,t,J＝6.2Hz),6.88(1H,dd,J＝9.0,2.3Hz),6.95-7.09(2H,m),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.0Hz),8.08(1H,d,J＝5.3Hz)

Example number 1021

N7- ((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) quinazoline-4, 7-diamine

Following general method 4, (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (75 mg,0.32 mmol) was reacted with 7-bromoquinazolin-4-amine (70 mg,0.31 mmol) and NaOtBu (60 mg,0.62 mmol) in THF (4 mL) at 60℃for 1h. After quenching, the crude product was purified by reverse phase flash chromatography (silica gel C18,5-50% (MeCN with 10mM ammonium bicarbonate)/water) to give the product as a colorless solid after lyophilization (19 mg, 15% yield).

¹ H NMR(500MHz,DMSO-d6)1.21-1.31(2H,m),1.63-1.71(3H,m),1.79-1.86(2H,m),2.13(3H,s),2.72-2.77(2H,m),4.07(2H,d,J＝6.1Hz),4.30(2H,d,J＝5.8Hz),6.49(1H,d,J＝2.3Hz),6.78(1H,d,J＝8.5Hz),6.86(1H,dd,J＝8.9,2.4Hz),6.92(1H,t,J＝5.8Hz),7.20(2H,s),7.69(1H,dd,J＝8.5,2.4Hz),7.85(1H,d,J＝9.0Hz),8.13(1H,s),8.16(1H,d,J＝2.4Hz)

[M+H] ⁺ ＝379.2

Example No. 4265

N6- ((2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

4- (((4-cyano-6- (trifluoromethyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester

Using general procedure 1a, tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (521 mg,2.42 mmol) was reacted with 2-chloro-6- (trifluoromethyl) isonicotinic acid nitrile (500 mg,2.42 mmol) for 1.5h. The crude product was purified by flash chromatography (silica gel, 0-50% etoac/isohexane) to give tert-butyl 4- (((4-cyano-6- (trifluoromethyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (496 mg, 53% yield) as a colorless oil.

[M-boc+H] ⁺ ＝286.2

¹ H NMR(500MHz,DMSO-d6)δ1.12-1.24(2H,m),1.40(9H,s),1.66-1.78(2H,m),1.90-2.05(1H,m),2.66-2.82(2H,m),3.91-4.05(2H,m),4.21(2H,d,J＝6.4Hz),7.80(1H,s),8.01(1H,s)。

2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) isonicotinic acid nitrile

According to general procedure 10, tert-butyl 4- (((4-cyano-6- (trifluoromethyl) pyridin-2-yl) oxy) methyl) piperidine-1-carboxylate (480 mg,1.26 mmol) was reacted at 90℃for 18h. After elution via SCX and concentration, the product was isolated as a clear orange liquid (255 mg, 72% yield).

[M+H] ⁺ ＝300.3

¹ H NMR(500MHz,DMSO-d6)δ1.24-1.36(2H,m),1.67-1.78(3H,m),1.83-1.94(2H,m),2.16(3H,s),2.74-2.83(2H,m),4.19(2H,d,J＝6.2Hz),7.79(1H,s),8.01(1H,s)。

(2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) pyridin-4-yl) methylamine

Following general method 3a, reduction of 2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) isonicotinic acid nitrile (115 mg,0.38 mmol) in MeOH (10 mL) was performed using Raney nickel for 1.5 h. The resulting solution was concentrated under reduced pressure to give the product as a colorless solid (112 mg, yield 91%).

[M+H] ⁺ ＝304.3

¹ H NMR (500 MHz, DMSO-d 6) δ1.27-1.40 (2H, m), 1.67-1.76 (3H, m), 1.86-1.97 (2H, m), 2.19 (3H, s), 2.78-2.86 (2H, m), 3.82 (2H, s), 4.13 (2H, d, J=6.0 Hz), 7.09 (1H, s), 7.48 (1H, s). NH was not observed ₂ 。

(6- (((2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid tert-butyl ester

Following general method 4, methyl tert-butyl (6-bromoisoquinolin-1-yl) carbamate (118 mg, 0.264 mmol) and (2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) pyridin-4-yl) methylamine (100 mg,0.330 mmol), naOtBu (63 mg,0.66 mmol) in THF (3 mL) were reacted at 60℃for 1h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (115 mg, 59% yield).

[M+H] ⁺ ＝546.4

Using general procedure 7b, at 18hDeprotection of tert-butyl (6- (((2- ((1-methylpiperidin-4-yl) methoxy) -6- (trifluoromethyl) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (110 mg,0.202 mmol) was performed at rt. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (72 mg, 79% yield).

[M+H] ⁺ ＝446.4

¹ H NMR(500MHz,DMSO-d6)δ1.20-1.32(2H,m),1.63-1.71(3H,m),1.78-1.85(2H,m),2.13(3H,s),2.71-2.77(2H,m),4.10(2H,d,J＝6.0Hz),4.49(2H,d,J＝6.2Hz),6.34(2H,s),6.46(1H,s),6.54(1H,d,J＝5.9Hz),6.86-6.92(2H,m),7.05(1H,s),7.48(1H,s),7.53-7.56(1H,m),7.89(1H,d,J＝9.0Hz)。

Example number 1026

(6- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-4-yl) methanol

6- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinoline-4-carboxylic acid methyl ester

Following general method 4, (6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (215 mg,0.84 mmol) was reacted with methyl 6-bromoisoquinoline-4-carboxylate (224 mg,0.84 mmol) and THF (10 mL) containing NaOtBu (2M in THF) (840 μl,1.68 mmol) at 60 ℃ for 1h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product as a yellow solid (200 mg, 40% yield).

[M+H] ⁺ ＝421.2

¹ H NMR(500MHz,DMSO-d6)1.43-1.57(2H,m),1.89-1.97(2H,m),1.97-2.05(1H,m),2.71-2.81(3H,m),2.91-3.02(2H,m),3.42-3.48(2H,m),3.92(3H,s),4.13(2H,d,J＝6.3Hz),4.43(2H,d,J＝5.6Hz),6.83(1H,d,J＝8.5Hz),7.32(1H,dd,J＝9.0,2.2Hz),7.71-7.75(1H,m),7.77(1H,dd,J＝8.5,2.5Hz),8.01(1H,d,J＝9.0Hz),8.08-8.13(1H,m),8.24(1H,d,J＝2.5Hz),8.80(1H,s),9.13(1H,s),9.29(1H,s)

Reduction using general method 3b methyl 6- (((6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinoline-4-carboxylate (45 mg,0.70 mmol) for 3h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (9 mg, 22% yield).

[M+H] ⁺ ＝393.2

¹ H NMR(500MHz,DMSO-d 6)1.20-1.32(2H,m),1.64-1.72(3H,m),1.79-1.87(2H,m),2.14(3H,s),2.72-2.79(2H,m),4.08(2H,d,J＝6.0Hz),4.34(2H,d,J＝5.6Hz),4.74(2H,d,J＝5.2Hz),5.18(1H,t,J＝5.4Hz),6.77-6.82(2H,m),7.05(1H,t,J＝5.7Hz),7.10(1H,dd,J＝8.9,2.1Hz),7.73(1H,dd,J＝8.5,2.5Hz),7.77(1H,d,J＝8.9Hz),8.17-8.23(2H,m),8.79(1H,s)。

Example number 1027

N6- ((2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) nicotinonitrile

Following general procedure 1a, (1-methylpiperidin-4-yl) methanol (382 mg,296 mmol) was reacted with 6-fluoro-2-methoxy nicotinonitrile (450 mg,2.96 mmol). By chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an orange oil (200 mg, 25% yield).

[M+H] ⁺ ＝262.3

¹ H NMR(500MHz,DMSO-d6)δ1.23-1.33(2H,m),1.63-1.74(3H,m),1.81-1.93(2H,m),2.15(3H,s),2.72-2.83(2H,m),3.98(3H,s),4.21(2H,d,J＝6.2Hz),6.54(1H,d,J＝8.4Hz),8.07(1H,d,J＝8.4Hz)。

(2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine

Following general method 3a, nitrile 2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) nicotinonitrile (198mg, 0.76 mmol) was reduced using Raney nickel for 1.5 h. The resulting solution was concentrated to give the product as a colorless solid (181 mg, yield 78%), which was used without purification.

[M+H] ⁺ ＝266.6

¹ H NMR(500MHz,DMSO-d6)δ1.22-1.32(2H,m),1.66-1.74(3H,m),1.79-1.87(2H,m),2.14(3H,s),2.73-2.80(2H,m),3.17(2H,d,J＝4.5Hz),3.32(2H,s),3.85(3H,s),4.08(2H,d,J＝6.1Hz),6.31(1H,d,J＝7.9Hz),7.60(1H,d,J＝7.9Hz)。

(6- (((2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (6-bromoisoquinolin-1-yl) carbamate (158 mg,0.56 mmol) was reacted with (2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methylamine (178 mg,0.56 mmol) and NaOtBu (108 mg,1.13 mmol) in THF (6 mL) at 60℃for 1h. After quenching, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (184 mg, 67% yield).

[M+H] ⁺ ＝466.4

Deprotection of methyl (6- (((2-methoxy-6- ((1-methylpiperidin-4-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (175 mg,0.376 mmol) was carried out at 60℃for 18h using general method 14 a. After elution via SCX, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 0.7 NH) ₃ MeOH)/DCM) to give the product as a colorless solid (130 mg, 83% yield).

[M+H] ⁺ ＝408.5

¹ H NMR(500MHz,DMSO-d6)δ1.20-1.32(2H,m),1.63-1.74(3H,m),1.78-1.87(2H,m),2.14(3H,s),2.72-2.79(2H,m),3.93(3H,s),4.09(2H,d,J＝6.0Hz),4.19(2H,d,J＝5.6Hz),6.25-6.29(2H,m),6.32(1H,d,J＝8.0Hz),6.44(1H,d,J＝2.3Hz),6.53(1H,t,J＝5.9Hz),6.56(1H,d,J＝5.9Hz),6.85(1H,dd,J＝9.0,2.4Hz),7.53-7.56(2H,m),7.84(1H,d,J＝9.0Hz)。

Example number 1028

N6- ((6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

2- (trifluoromethyl) imidazo [1,2-a ] pyridine-7-carboxylic acid ethyl ester

To 2-amino isonicotinic acid methyl ester(3.05 g,20.0 mmol) and K ₂ CO ₃ (5.54 g,40.1 mmol) to a stirred suspension in EtOH (120 mL) was added 3-bromo-1, 1-trifluoropropan-2-one (2.7 mL,26 mmol) and the resulting suspension was heated to 80℃and held for 72h. The reaction mixture was cooled, filtered and concentrated. The residue was dissolved in EtOH (120 mL), HCl (12M, 170. Mu.L, 2.04 mmol) was added, and the mixture was heated at 70℃overnight. The reaction was cooled to rt and filtered. The filtrate was concentrated and purified by flash chromatography (silica gel, 0-5% (containing 0.7M NH) ₃ MeOH)/DCM) to give (1.37 g, 41% yield) as a pale yellow solid.

[M+H]+＝259.3

2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylic acid ethyl ester

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Following general procedure 3e, at 5 bar H ₂ (g) Next, 2- (trifluoromethyl) imidazo [1,2-a ] is allowed to stand]Pyridine-7-carboxylic acid ethyl ester (1.37 g,1.06 mmol) was reacted in EtOH (50 mL) and HCl (12M, 470. Mu.L, 5.64 mmol) at 70℃for 3h. The crude material was partitioned between DCM (150 mL) and saturated NaHCO ₃ Between aqueous solutions (150 mL), the aqueous solution was extracted with additional DCM (150 mL) and the combined organics were concentrated to give the product as a pale yellow solid (1.49 g, quantitative yield).

(2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol

Following general method 3b, ethyl 2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridine-7-carboxylate (1.41 g,3.23 mmol) was reacted for 30min. The product was isolated as a pale yellow solid (1.18 g, 93% yield) and used without further purification.

[M+H] ⁺ ＝221.2

¹ H NMR(500MHz,DMSO-d6)1.53-1.69(1H,m),1.93-2.10(1H,m),2.40(1H,dd,J＝16.7,10.6Hz),2.85(1H,ddd,J＝16.7,5.2,1.6Hz),3.18(1H,d,J＝5.1Hz),3.36-3.48(2H,m),3.84-3.95(1H,m),4.05-4.18(1H,m),4.75(1H,t,J＝5.3Hz),7.64(1H,s)

6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) nicotinonitrile

(2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1, 2-a) using general procedure 1b]Pyridin-7-yl) methanol (400 mg,1.82 mmol) was reacted with 6-fluoronicotinonitrile (266 mg,2.18 mmol) for 22h. The solids were removed by filtration and the filtrate was concentrated. By flash chromatography (silica gel, 0-5% (containing 0.7M NH) ₃ MeOH)/DCM) to afford 6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1, 2-a) as an off-white solid]Pyridin-7-yl) methoxy) nicotinonitrile (182 mg, 30% yield).

[M+H] ⁺ ＝323.2

¹ H NMR(500MHz,DMSO-d6)1.72-1.84(1H,m),2.12-2.20(1H,m),2.45-2.48(1H,m),2.59(1H,dd,J＝16.5,10.9Hz),2.99(1H,dd,J＝16.5,5.1Hz),3.91-4.01(1H,m),4.12-4.20(1H,m),4.39(2H,d,J＝6.5Hz),7.06(1H,d,J＝8.7Hz),7.68(1H,s),8.18(1H,dd,J＝8.6,2.4Hz),8.71(1H,d,J＝2.3Hz)

(6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methylamine

Using general procedure 3a, reduction of nitrile 6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) nicotinonitrile (180 mg,0.56 mmol) was performed using a Raney nickel cartridge for 2h. The reaction mixture was concentrated to give the product as a pale yellow oil (92 mg, 47% yield).

[M+H] ⁺ ＝327.3

¹ H NMR(500MHz,DMSO-d6) 1.70-1.85 (1 h, m), 2.11-2.21 (1 h, m), 2.36-2.46 (1 h, m), 2.56 (1 h, dd, j=16.6, 10.8 Hz), 2.97 (1 h, ddd, j=16.6, 5.2,1.5 Hz), 3.65 (2 h, s), 3.91-4.00 (1 h, m), 4.12-4.19 (1 h, m), 4.26 (2 h, d, j=6.6 Hz), 6.80 (1 h, d, j=8.4 Hz), 7.67 (1 h, d, j=1.4 Hz), 7.70 (1 h, dd, j=8.5, 2.5 Hz), 8.06 (1 h, d, j=2.4 Hz), (2 x exchangeable protons are not visible).

(6- (((6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-3-yl) methylamine (90 mg,0.23 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (66 mg,0.23 mmol) and NaOtBu (45 mg,0.47 mmol) in THF (2 mL) at 60℃for 1h. After quenching and concentration, the extract was purified by flash chromatography (silica gel, 0-10% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (54 mg, 42% yield).

[M+H] ⁺ ＝527.2

Using general procedure 14a (6- (((6- ((2- (trifluoromethyl) -5,6,7, 8-tetrahydroimidazo [1, 2-a)) ]Pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (50 mg,0.10 mmol) was deprotected for 72h. After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to give the product as an off-white solid (15 mg, 32% yield).

[M+H] ⁺ ＝469.4

¹ H NMR(500MHz,DMSO-d6)1.69-1.81(1H,m),2.11-2.20(1H,m),2.39-2.47(2H,m),2.96(1H,dd,J＝16.4,5.0Hz),3.91-4.00(1H,m),4.11-4.18(1H,m),4.26(2H,d,J＝6.5Hz),4.31(2H,d,J＝5.4Hz),6.50(2H,s),6.56(1H,d,J＝2.4Hz),6.60(1H,d,J＝6.0Hz),6.76-6.80(1H,m),6.84(1H,d,J＝8.5Hz),6.89(1H,dd,J＝9.0,2.3Hz),7.54(1H,d,J＝6.0Hz),7.66(1H,d,J＝1.5Hz),7.74(1H,dd,J＝8.4,2.5Hz),7.88(1H,d,J＝9.0Hz),8.20(1H,d,J＝2.4Hz)

Examples 1029 and 1030 (enantiomers)

N5- ((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

(5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-3-yl) methylamine (190 mg,0.74 mmol) was reacted with methyl (5-bromoisoquinolin-1-yl) carbamate (207 mg,0.74 mmol) and THF (4 mL) containing NaOtBu (141 mg,1.47 mmol) at 60℃for 1h. After quenching, the extract was purified by flash chromatography (silica gel, 0-10% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product as an off-white solid (179 mg, 53% yield).

[M+H] ⁺ ＝459.4

¹ H NMR(500MHz,DMSO-d6)δ1.64-1.78(1H,m),2.07-2.16(1H,m),2.31-2.40(1H,m),2.44-2.51(1H,m),2.87-2.95(1H,m),3.66(3H,s),3.83-3.92(1H,m),4.06-4.12(1H,m),4.24(2H,d,J＝6.6Hz),4.44(2H,d,J＝5.8Hz),6.66(1H,d,J＝7.7Hz),6.79-6.83(2H,m),6.98(1H,d,J＝1.3Hz),7.02 -7.07(1H,m),7.25(1H,d,J＝8.4Hz),7.30-7.35(1H,m),7.74(1H,dd,J＝8.5,2.4Hz),7.96(1H,d,J＝6.0Hz),8.16-8.26(2H,m),9.85(1H,s)

Chiral separation by chiral SFC on Waters prep 15 (UV detection by DAD at 210-400nm, 40 ℃,120 bar, flow rate 15mL/min, using 50% 1:1MeOH: meCN, 0.1% ammonia) afforded (5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (114 mg,0.25 mmol) as a white solid (R) - (5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (30 mg,0.062mmol, yield 8.5%)

[M+H] ⁺ ＝459.4

And methyl (S) - (5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (28.5 mg,0.057mmol, 7.8% yield) as a white solid.

[M+H] ⁺ ＝459.4

(R) -N5- ((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (example No. 1029)

(R) - (5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)) using general procedure 14a over 20h]Pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (30 mg,0.065 μmol). After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to give (R) -N5- ((6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a) as an off-white solid]Pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (20 mg, 73% yield).

[M+H] ⁺ ＝401.2

¹ H NMR(500MHz,DMSO-d6)δ1.66-1.78(1H,m),2.10-2.16(1H,m),2.32-2.42(1H,m),2.47-2.54(1H,m),2.89-2.98(1H,m),3.85-3.94(1H,m),4.05-4.12(1H,m),4.24(2H,d,J＝6.6Hz),4.40(2H,d,J＝5.7Hz),6.58(1H,d,J＝7.8Hz),6.66(2H,s),6.71(1H,t,J＝6.0Hz),6.80(1H,d,J＝8.5Hz),6.86(1H,d,J＝1.3Hz),7.03(1H,d,J＝1.3Hz),7.17(1H,app t,J＝8.0Hz),7.20(1H,d,J＝6.2Hz),7.35(1H,d,J＝8.3Hz),7.70-7.75(2H,m),8.19(1H,d,J＝2.4Hz)

(S) -N5- ((6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (example No. 1030)

(S) - (5- (((6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)) using general procedure 14a over 20h]Pyridin-7-yl) methoxy) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (25 mg,0.055 mmol). After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH ₃ MeOH)/DCM) to give (S) -N5- ((6- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a) as an off-white solid]Pyridin-7-yl) methoxy) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (19 mg, 84% yield).

[M+H] ⁺ ＝401.4

¹ H NMR(500MHz,DMSO-d6)δ1.65-1.78(1H,m),2.10-2.16(1H,m),2.31-2.42(1H,m),2.46-2.54(1H,m),2.88-2.97(1H,m),3.83-3.94(1H,m),4.04-4.12(1H,m),4.24(2H,d,J＝6.6Hz),4.40(2H,d,J＝5.7Hz),6.57(1H,d,J＝7.8Hz),6.61(2H,s),6.69(1H,t,J＝6.0Hz),6.80(1H,d,J＝8.5Hz),6.84(1H,d,J＝1.3Hz),7.02(1H,d,J＝1.3Hz),7.16(1H,app t,J＝8.0Hz),7.19(1H,d,J＝6.2Hz),7.34(1H,d,J＝8.3Hz),7.70-7.75(2H,m),8.19(1H,d,J＝2.4Hz)

Examples 4267 and 4412 (enantiomer) N6- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

N1- (2, 4-Dimethoxybenzyl) -N5- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine

Using general procedure 4, (2- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl methoxy) pyridin-4-yl) methylamine (108 mg,0.42 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (129 mg,0.46 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (80 mg,0.84 mmol) at 60℃for 3h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH/DCM) to give the racemate as an off-white solid.

The racemate was purified by SFC reverse phase chiral HPLC on Waters prep 15 (UV detection by DAD at 210-400nm, 40 ℃,120 bar, LUX A2 10X250mm,5 μm column, flow rate 15mL/min-1, 50% MeOH). The samples were lyophilized to give enantiomer 1 and enantiomer 2 as colorless solids. Absolute configuration is arbitrarily assigned.

Enantiomer 1:

(R) - (6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

(43 mg, 22% yield)

[M+H] ⁺ = 459.0;100% ee (diode array).

Enantiomer 2:

(S) - (6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

(43 mg, 22% yield)

[M+H] ⁺ = 459.0;100% ee (diode array).

(S-1, 6-diamine- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine (enantiomer 2, example number 4267)

Deprotection of methyl (S) - (6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (43 mg,0.094 mmol) was performed using general method 14a for 24h. After quenching and elution via SCX, the product was lyophilized to give the product as a white fluffy solid (30 mg, 80% yield).

[M+H] ⁺ ＝401.5

¹ H NMR(500MHz,DMSO-d6)δ1.65-1.75(1H,m),2.07-2.15(1H,m),2.29-2.41(1H,m),2.43-2.47(1H,m),2.86-2.94(1H,m),3.82-3.91(1H,m),4.02-4.10(1H,m),4.24(2H,d,J＝6.6Hz),4.39(2H,d,J＝6.1Hz),6.31(2H,s),6.44(1H,d,J＝2.4Hz),6.53(1H,d,J＝5.8Hz),6.79(1H,d,J＝1.3Hz),6.81(1H,s),6.85(1H,t,J＝6.2Hz),6.88(1H,dd,J＝9.0,2.4Hz),6.94-7.04(2H,m),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.1Hz),8.08(1H,d,J＝5.3Hz)。

(R) -N6- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine (enantiomer 1, example number 4412)

Deprotection of methyl (R) - (6- (((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (43 mg,0.094 mmol) was performed using general method 14a for 24h. After quenching and elution via SCX, the product was lyophilized to give the product as a white fluffy solid (43 mg, 93% yield).

[M+H] ⁺ ＝401.5

¹ H NMR(500MHz,DMSO-d6)1.63-1.79(1H,m),2.05-2.18(1H,m),2.30-2.39(1H,m),2.45-2.50(1H,m),2.85-2.96(1H,m),3.78-3.93(1H,m),4.01-4.13(1H,m),4.24(2H,d,J＝6.5Hz),4.39(2H,d,J＝6.0Hz),6.26-6.35(2H,m),6.44(1H,d,J＝2.3Hz),6.53(1H,d,J＝5.8Hz),6.78-6.93(4H,m),6.96-7.04(2H,m),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.0Hz),8.08(1H,d,J＝5.3Hz)。

Example number 1033

N6- ((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) isoquinoline-1, 6-diamine

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Following general method 4, 5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine (73 mg,0.31 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (90 mg,0.32 mmol) and THF (5 mL) containing NaOtBu (60 mg,0.62 mmol) at 60 ℃ for 2h. After quenching the reaction mixture and concentrating, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (120 mg, 86% yield).

[M+H] ⁺ ＝435.4

Deprotection of methyl (6- (((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) amino) isoquinolin-1-yl) carbamate (120 mg, 0.247 mmol) was carried out using general method 14a for 20h. By reverse phase flash chromatography (silica gel, C18,0-100% THF/10mM NH) ₄ HCO ₃ ) The crude product was purified to give the product as a pale yellow solid (22 mg, 22% yield).

[M+H] ⁺ ＝377.2

¹ H NMR(500MHz,DMSO-d6)δ1.10-1.20(2H,m),1.41-1.52(1H,m),1.61-1.69(2H,m),1.73-1.82(2H,m),2.12(3H,s),2.67 -2.77(2H,m),3.06-3.12(2H,m),4.12(2H,d,J＝5.6Hz),6.34(2H,s),6.42-6.48(2H,m),6.50(1H,t,J＝5.6Hz),6.53(1H,d,J＝2.3Hz),6.58(1H,d,J＝5.8Hz),6.86(1H,dd,J＝9.1,2.3Hz),7.37(1H,dd,J＝8.6,2.4Hz),7.54(1H,d,J＝5.9Hz),7.84(1H,d,J＝9.1Hz),7.98(1H,d,J＝2.4Hz)。

Example No. 4268

4-chloro-N6- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

(4-chloro-6- (((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Using general procedure 4, (2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methylamine (23 mg,0.10 mmol) was reacted with methyl (6-bromo-4-chloroisoquinolin-1-yl) carbamate (36 mg,0.10 mmol) and NaOtBu (40 mg,0.38 mmol) in THF (5 mL) at 40℃and stirred for 5h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow solid (38 mg, 71% yield).

[M+H] ⁺ ＝470.2/472.2

4-chloro-N6- ((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine, HCl

The general procedure 14a was used for the preparation of (4-chloro-6- "Deprotection of methyl (((2- ((1-methylpiperidin-4-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamate (35 mg,0.06 mol) was continued for 48h. The reaction was cooled and concentrated. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colourless solid (19 mg, 65%).

[M+H] ⁺ ＝412.1

¹ H NMR(500MHz,DMSO-d6)1.49-1.63(2H,m),1.85-1.92(3H,m),1.93-2.03(1H,m),2.69(3H,s),2.80-3.02(3H,m),4.13(2H,d,J＝6.4Hz),4.43(2H,d,J＝6.1Hz),6.66(1H,d,J＝2.3Hz),6.75-6.82(3H,m),6.98(1H,dd,J＝9.1,2.4Hz),7.01(1H,dd,J＝5.3,1.4Hz),7.35(1H,t,J＝6.2Hz),7.67(1H,s),7.99(1H,d,J＝9.1Hz),8.09(1H,d,J＝5.2Hz),10.20(1H,s)。

Example number 4270

N6- ((2- ((3-methyl-3-azabicyclo [3.2.1] oct-8-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

8- (((4-cyanopyridin-2-yl) oxy) methyl) -3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester

Tert-butyl-8- (hydroxymethyl) -3-azabicyclo [3.2.1] octane-3-carboxylate (300 mg,1.24 mmol) was reacted with 2-fluoroisonicotinic nitrile (152 mg,1.24 mmol) using general method 1b for 7 days. The reaction was filtered and the filtrate purified by flash chromatography (silica gel, 0-50% EtOAc/isohexane) to give the product as a colourless crystalline solid (355 mg, 81% yield).

[M+Na] ⁺ ＝366.1

¹ H NMR(500MHz,DMSO-d6)δ1.39(9H,s),1.42-1.53(2H,m),1.66-1.77(2H,m),2.05-2.12(1H,m),2.13-2.23(2H,m),3.02(1H,d,J＝12.9Hz),3.15(1H,d,J＝13.0Hz),3.48(1H,d,J＝13.2Hz),3.54(1H,d,J＝13.0Hz),4.64(2H,d,J＝7.6Hz),7.37-7.43(2H,m),8.41(1H,dd,J＝5.1,0.9Hz)ppm。

2- ((3-methyl-3-azabicyclo [3.2.1] oct-8-yl) methoxy) isonicotinic acid nitrile

Tert-butyl 8- (((4-cyanopyridin-2-yl) oxy) methyl) -3-azabicyclo [3.2.1] octane-3-carboxylate (350 mg,1.02 mmol) was reacted for 2h following general method 10. The product was isolated as a colourless solid (205 mg, 77% yield).

[M+H] ⁺ ＝258.1

(2- ((3-methyl-3-azabicyclo [3.2.1] oct-8-yl) methoxy) pyridin-4-yl) methylamine

Following general procedure 3a, reduction of nitrile 2- ((3-methyl-3-azabicyclo [3.2.1] oct-8-yl) methoxy) isonicotinic nitrile (205 mg,0.797 mmol) was performed over 3h using raney nickel. The reaction was concentrated to give the product as a clear colorless oil (190 mg, 85% yield).

[M+H] ⁺ ＝262.2

¹ H NMR(500MHz,DMSO-d6)1.58-1.72(4H,m),1.88-2.02(3H,m),2.10-2.16(2H,m),2.16(3H,s),2.31-2.36(2H,m),2.40(2H,dd,J＝11.1,3.6Hz),3.68(2H,s),4.53(2H,d,J＝7.5Hz),6.78(1H,s),6.91(1H,dd,J＝5.3,1.4Hz),8.04(1H,d,J＝5.3Hz)ppm。

(6- (((2- ((3-methyl-3-azabicyclo [3.2.1] oct-8-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (2- ((3-methyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) methoxy) pyridin-4-methyl amine (90 mg,0.34 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (97 mg,0.34 mmol) and THF (6 mL) containing NaOtBu (66 mg,0.69 mmol) at 60℃for 3h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow gum (99 mg, 53% yield).

[M+H] ⁺ ＝462.2

¹ H NMR(500MHz,DMSO-d6)δ1.58-1.70(4H,m),1.91-1.98(1H,m),2.07-2.12(2H,m),2.15(3H,s),2.28-2.35(2H,m),2.35-2.45(2H,m),3.65(3H,s),4.42(2H,d,J＝6.2Hz),4.52(2H,d,J＝7.5Hz),6.52-6.63(1H,m),6.76(1H,s),6.95-6.99(1H,m),7.08(1H,d,J＝9.0Hz),7.13-7.26(1H,m),7.29 -7.47(1H,m),7.76(1H,d,J＝9.1Hz),7.91-7.99(1H,m),8.10(1H,dd,J＝5.3,0.7Hz),9.72(1H,s)ppm。

Using general procedure 14a (6- (((2- ((3-methyl-3-azabicyclo [ 3.2.1)]Oct-8-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (95 mg,0.21 mmol) was deprotected for 20h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless solid (9.0 mg, 10% yield).

[M+H] ⁺ ＝404.2

¹ H NMR(DMSO,500MHz)δ1.55-1.69(4H,m),1.92-1.99(1H,m),2.08-2.12(2H,m),2.14(3H,s),2.27-2.33(2H,m),2.38(2H,dd,J＝11.2,3.6Hz),4.37(2H,d,J＝6.2Hz),4.51(2H,d,J＝7.5Hz),6.32(2H,s),6.43(1H,d,J＝2.4Hz),6.53(1H,d,J＝5.8Hz),6.75(1H,s),6.83(1H,t,J＝6.3Hz),6.88(1H,dd,J＝9.0,2.4Hz),6.97(1H,dd,J＝5.3,1.4Hz),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.1Hz),8.09(1H,d,J＝5.3Hz)ppm。

Example No. 4275

1- (5- (((4- (((1-aminoisoquinolin-6-yl) amino) methyl) pyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1] hept-2-yl) ethan-1-one

(6- (((2- ((2-acetyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, 1- (5- (((4- (aminomethyl) pyridin-2-yl) oxy) methyl) -2-azabicyclo [ 2.2.1)]Hept-2-yl) ethan-1-one (125 mg,0.45 mmol) was reacted with methyl (6-bromoisoquinolin-1-yl) carbamate (128 mg,0.45 mmol) and NaOtBu (26 mg,0.27 mmol) in THF (6 mL) at 60℃for 2h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-15% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colourless glass (148 mg, 65% yield).

[M+H] ⁺ ＝476.2

Using general procedure 14a (6- (((2- ((2-acetyl-2-azabicyclo [ 2.2.1)]Hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (148 mg,0.31 mmol) was deprotected for 16h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ The crude product was purified with EtOAc/IPA (3:1))/hexane. Lyophilization afforded the product as a colorless solid (91 mg, 68% yield).

[M+H] ⁺ ＝418.2

¹ H NMR (500 MHz, DMSO-d 6) 1.05-1.11 (1H, m, minor), 1.15-1.20 (1H, m, major), 1.50-1.55 (1H, m, minor), 1.58-1.63 (1H, m), 1.69-1.73 (1H, m, major), 1.82 (3H, s, minor), 1.92 (3H, s, major), 1.78-1.96 (1H, m), 2.40-2.49 (1H, m), 2.54-2.62 (1H, m), 2.99-3.03 (1H, m, minor), 3.23-3.28 (2 XH, m, major), 3.34-3.38 (1H, m, secondary), 4.03-4.17 (1H, m and 1H, m, secondary), 4.20-4.26 (1H, m, primary), 4.32-4.36 (1H, m), 4.38 (2H, d, j=6.4 Hz), 6.31 (2H, s), 6.42-6.43 (1H, m), 6.53 (1H, dd, j=5.9, 2.3 Hz), 6.75 (1H, s), 6.82-6.86 (1H, m), 6.88 (1H, dd, j=9.0, 2.3 Hz), 6.98 (1H, dd, j=5.3, 1.4 Hz), 7.54 (1H, d, j=5.8 Hz), 7.87 (1H, d, j=9.0 Hz), 8.06-8.09 (1H, m)

Example No. 4274

1- (5- (((4- (((1-aminoisoquinolin-5-yl) amino) methyl) pyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1] hept-2-yl) ethan-1-one

(5- (((2- ((2-acetyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, 1- (5- (((4- (aminomethyl) pyridin-2-yl) oxy) methyl) -2-azabicyclo [ 2.2.1)]Hept-2-yl) ethan-1-one (125 mg,0.45 mmol) was reacted with methyl (5-bromoisoquinolin-1-yl) carbamate (128 mg,0.45 mmol) and NaOtBu (90 mg,0.94 mmol) in THF (6 mL) at 60℃for 5h. After quenching the reaction, it was purified by flash chromatography (silica gel, 0-15% (containing 0.7M NH) ₃ MeOH)/DCM) was purified. Lyophilization afforded the product as a colorless solid (140 mg, 62% yield).

[M+H] ⁺ ＝476.2

Using general procedure 14a (5- (((2- ((2-acetyl-2-azabicyclo [ 2.2.1)]Hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (140 mg,0.29 mmol) was deprotected for 18h. After quenching the reaction mixture, it was purified by flash chromatography (silica gel, 0-15% (containing 0.7M NH) ₃ MeOH)/DCM) was purified. Lyophilization afforded the product as a colorless solid (70 mg, 56% yield).

[M+H] ⁺ ＝418.2

¹ H NMR (500 MHz, DMSO-d 6) 1.04-1.09 (1H, m, minor), 1.13-1.19 (1H, m, major), 1.49-1.54 (1H, m, minor), 1.56-1.63 (1H, m), 1.68-1.73 (1H, m, major), 1.81 (3H, s, minor), 1.92 (3H, s, major), 1.78-1.96 (1H, m), 2.40-2.48 (1H, m), 2.52-2.61 (1H, m), 2.98-3.03 (1H, m, major), 3.22-3.27 (1H, m), 3.29-3.37 (1H, m, minor), 4.02-4.24 (2H, m), 4.30-4.36 (1H, m), 4.45 (2H, d, j=6.0 Hz), 6.38 (1H, d, j=7.7 Hz), 6.53 (2H, s), 6.72 (1H, s), 6.78-6.83 (1H, m), 6.98 (1H, dd, j=5.2, 1.4 Hz), 7.09-7.14 (1H, m), 7.20 (1H, d, j=6.1 Hz), 7.34 (1H, d, j=8.3 Hz), 7.77 (1H, d, j=6.0 Hz), 8.06 (1H, t, j=5.1 Hz)

Example No. 4277

N6- ((2- ((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

2- ((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) isonicotinic acid nitrile

Following general procedure 10, 5- (((4-cyanopyridin-2-yl) oxy) methyl) -2-azabicyclo [2.2.1]Heptane-2-carboxylic acid tert-butyl esterThe ester (500 mg,1.52 mmol) was reacted for 2h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a clear colorless oil (272 mg, 58% yield).

[M+H] ⁺ ＝244.1

¹ H NMR(500MHz,DMSO-d6)1.14-1.21(1H,m),1.29-1.36(1H,m),1.59-1.69(2H,m),2.21(3H,s),2.26-2.34(2H,m),2.36-2.41(1H,m),2.57-2.66(1H,m),2.93-2.99(1H,m),4.20-4.28(1H,m),4.34-4.42(1H,m),7.33-7.42(2H,m),8.40(1H,d,J＝5.4Hz)。

(2- ((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) pyridin-4-yl) methylamine

According to general procedure 3a, reduction of nitrile 2- ((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) isonicotinic nitrile (270 mg,1.11 mmol) was performed over 2h using Raney nickel. The reaction was concentrated to give the product as a clear colorless oil (280 mg, 97% yield).

[M+H] ⁺ ＝248.1

¹ H NMR(500MHz,DMSO-d6)1.15-1.23(1H,m),1.31-1.38(1H,m),1.59-1.72(2H,m),2.23(3H,s),2.26-2.40(3H,m),2.62-2.69(1H,m),2.95-3.03(1H,m),3.06-3.45(2H,m),3.68(2H,s),4.17(1H,dd,J＝10.8,9.3Hz),4.32(1H,dd,J＝10.7,6.7Hz),6.76(1H,s),6.91(1H,d,J＝5.2Hz),8.02(1H,d,J＝5.2Hz)。

(6- (((2- ((2-methyl-2-azabicyclo [2.2.1] hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (2- ((2-methyl-2-azabicyclo [ 2.2.1)]Hept-5-yl-methoxy) pyridin-4-yl) methylamine (130 mg,0.53 mmol) and methyl (6-bromoisoquinolin-1-yl) carbamate (148 mg,0.53 mmol) and NaOtBu (101 mg,1.05 m) mol) of THF (6 mL) was reacted at 60℃for 2h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a colorless oil (189 mg, 77% yield).

[M+H] ⁺ ＝448.5

Using general procedure 14a over 24h (6- (((2- ((2-methyl-2-azabicyclo [2.2.1 ])]Hept-5-yl) methoxy) pyridin-4-yl) methyl) amino) isoquinolin-1-yl) methyl carbamate (180 mg,0.40 mmol). After quenching and elution via SCX, the sample was purified by flash chromatography (silica gel, 0-100% (containing 10% NH) ₃ MeOH)/DCM) was purified. Lyophilization afforded the product as a pale yellow solid (74 mg, 45% yield).

[M+H] ⁺ ＝390.2

¹ H NMR(500MHz,DMSO-d6)1.11-1.18(1H,m),1.27-1.32(1H,m),1.56-1.67(2H,m),2.19(3H,s),2.22-2.32(2H,m),2.32-2.36(1H,m),2.56-2.61(1H,m),2.91-2.96(1H,m),4.11-4.19(1H,m),4.30(1H,dd,J＝10.8,6.7Hz),4.37(2H,d,J＝6.2Hz),6.32(2H,s),6.43(1H,d,J＝2.4Hz),6.53(1H,dd,J＝5.9,0.7Hz),6.72-6.76(1H,m),6.83(1H,t,J＝6.3Hz),6.88(1H,dd,J＝9.0,2.4Hz),6.97(1H,dd,J＝5.3,1.4Hz),7.54(1H,d,J＝5.8Hz),7.87(1H,d,J＝9.1Hz),8.05-8.08(1H,m)。

Example No. 4285

4-chloro-N6- ((2- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-4-yl) methyl) isoquinoline-1, 6-diamine

N- [ 4-chloro-6- [ [2- [ (1-methyl-4-piperidinyl) methylamino ] -4-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

Following general procedure 4, methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (44 mg,0.13 mmol) and 4- (aminomethyl) -N- [ (1-methyl-4-piperidinyl) methyl]Pyridin-2-amine (30 mg,0.13 mmol) and THF (5 mL) containing NaOtBu (168 mg,0.51 mmol) were reacted at 40℃for 9h. The reaction was cooled to rt via Filtered, washed with EtOAc (50 mL), DCM (50 mL), and MeOH (50 mL). The filtrate was concentrated to give the product as a brown oil (24 mg, 40% yield).

[M+H] ⁺ ＝469.1

4-chloro-N6- [ [2- [ (1-methyl-4-piperidinyl) methylamino ] -4-pyridinyl ] methyl ] isoquinoline-1, 6-diamine

Deprotection of methyl N- [ 4-chloro-6- [ [2- [ (1-methyl-4-piperidinyl) methylamino ] -4-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamate (20 mg,0.04 mmol) was carried out using general method 14b for 12h. After quenching and elution via SCX, the crude product was purified via automated preparative HPLC (2-60% mass orientation over 20min in alkaline mobile phase). Lyophilization afforded the product as an off-white solid (5 mg, 24% yield).

[M+H] ⁺ ＝411.1

¹ H NMR(DMSO,400MHz)δ1.03-1.17(2H,m),1.35-1.46(1H,m),1.59(2H,d,J＝10.7Hz),1.70(2H,td,J＝11.5,2.6Hz),2.09(3H,s),2.63-2.72(2H,m),3.05(2H,d,J＝6.3Hz),4.25(2H,d,J＝6.0Hz),6.42(1H,s),6.44(1H,dd,J＝5.2,1.6Hz),6.49(1H,t,J＝5.8Hz),6.54(2H,s),6.64(1H,d,J＝2.4Hz),6.91(1H,dd,J＝9.0,2.4Hz),7.12(1H,d,J＝6.1Hz),7.64(1H,s),7.86(1H,d,J＝5.3Hz),7.92(1H,d,J＝9.0Hz)

Example number 2208

N5- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

N- [ [ 2-fluoro-4- (hydroxymethyl) phenyl ] methyl ] carbamic acid tert-butyl ester

Following general method 3c, 2-fluoro-4- (hydroxymethyl) benzonitrile (1.9 g,12.57 mmol) was reduced over 72 h. The reaction mixture is passed throughFiltered, concentrated and redissolved in THF (100 mL). Adding Boc ₂ O (2.7 g,12.57 mmol) and the reaction stirred at 60℃for 18h. The reaction was concentrated and the crude product purified by flash chromatography (silica gel, 0-8% meoh/DCM) to give the product as an off-white solid (1.9 g, 59% yield).

¹ H NMR(DMSO,400MHz)δ1.39(9H,s),4.14(2H,d,J＝6.1Hz),4.47(2H,d,J＝5.6Hz),5.26(1H,t,J＝5.8Hz),7.08(2H,t,J＝10.3Hz),7.24(1H,t,J＝7.8Hz),7.35(1H,t,J＝6.2Hz)

N- [ [4- (chloromethyl) -2-fluoro-phenyl ] methyl ] carbamic acid tert-butyl ester

Chlorination of tert-butyl N- [ [ 2-fluoro-4- (hydroxymethyl) phenyl ] methyl ] carbamate (900 mg,3.33 mmol) was performed using general method 6 a. The crude product was purified by flash chromatography (silica gel, 20-80% etoac/petroleum ether 60-80) to give the product as an off-white solid (705 mg, 77% yield).

[M-tBu+H] ⁺ ＝218.0

N- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methyl ] carbamic acid tert-butyl ester

Following general method 5a, 2- (1-methyl-1H-imidazol-2-yl) ethan-1-ol (55 mg,0.44 mmol) was reacted with tert-butyl N- [ [4- (chloromethyl) -2-fluoro-phenyl ] methyl ] carbamate (100 mg,0.37 mmol) for 3H. The crude product was purified by flash chromatography (silica gel, 0-12% MeOH/DCM) to give the product as an off-white solid (52 mg, 39% yield).

[M+H] ⁺ ＝364.1

[ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methylamine

Following general procedure 7a, N- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] at rt]Phenyl group]Methyl group]Boc deprotection of tert-butyl carbamate (52 mg,0.14 mmol) continued for 45min. The reaction mixture was concentrated. The crude material was dissolved in MeOH (2 mL) and passed through bicarbonate resin, washing with MeOH (10 mL). The filtrate was concentrated and treated with Et ₂ O (2X 10 mL) was triturated to give the product as an off-white solid (37 mg, 98% yield).

[M+H] ⁺ ＝264.0

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

Following general procedure 4, 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (35 mg,0.09 mmol) and [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ]]Phenyl group]Methylamine (25 mg,0.09 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (62 mg,0.19 mmol) at 60 ℃The reaction was carried out for 6 hours. Quenching and passing throughAfter filtration, the mixture was purified by flash chromatography (silica gel, 0-24% (containing 10% NH) ₃ MeOH)/DCM) to give the product as a yellow gum (21 mg, 40% yield).

[M+H] ⁺ ＝556.3

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine (25 mg,0.04 mmol) was deprotected in TFA (1 mL,12.98 mmol) and heated to 50deg.C for 25min using general procedure 12. The crude product was purified via automated prep HPLC (2-60% mass orientation over 20min in alkaline mobile phase). Lyophilization afforded the product N5- [ [ 2-fluoro-4- [2- (1-methylimidazol-2-yl) ethoxymethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine (1 mg, 5% yield) as an off-white solid.

[M+H] ⁺ ＝406.1

¹ H NMR(CDCl ₃ ,400MHz)δ2.99(2H,t,J＝6.8Hz),3.59(3H,s),3.87(2H,t,J＝6.9Hz),4.50(2H,s),4.53(2H,d,J＝5.2Hz),4.68(1H,s),5.14(2H,s),6.73(1H,d,J＝7.7Hz),6.79(1H,d,J＝1.4Hz),6.93(1H,d,J＝1.4Hz),6.96-7.06(3H,m),7.15(1H,d,J＝8.3Hz),7.33(2H,t,J＝7.9Hz),7.93(1H,d,J＝6.1Hz)

Example number 2183

N5- [ [ 2-fluoro-4- (2-N-morpholinoethyl) phenyl ] methyl ] isoquinoline-1, 5-diamine

2-fluoro-4- (2-N-morpholinyl-2-oxo-ethyl) benzonitrile

Following general method 8, 2- (4-cyano-3-fluorophenyl) acetic acid (150 mg,0.84 mmol) was coupled with morpholine (87 μl,1.0 mmol). The crude product was purified by flash chromatography (silica gel, 0-20% meoh/DCM) to give the product as a white solid (123 mg, 59% yield).

[M+H] ⁺ ＝249.0

[ 2-fluoro-4- (2-N-morpholinoethyl) phenyl ] methylamine

The overall reduction of 2-fluoro-4- (2-N-morpholino-2-oxo-ethyl) benzonitrile (120 mg,0.48 mmol) of amide and nitrile was carried out over 2h using general method 3 b. The product was isolated as a yellow solid (165 mg, quantitative yield) and used without further purification.

[M+H] ⁺ ＝239.1

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- (2-N-morpholinoethyl) phenyl ] methyl ] isoquinoline-1, 5-diamine

Following general procedure 4, 2-fluoro-4- (2-N-morpholinoethyl) phenyl]Methylamine (50.0 mg,0.21 mmol) and 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinoline-1-amine (117 mg,0.31 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (138 mg,0.42 mmol) were reacted at 60℃for 2h. The reaction was quenched with AcOH (43. Mu.L, 0.72 mmol) via Filtered, washed with EtOAc (50 mL) and EtOAc/MeOH (5:1, 60 mL) and concentrated. Purification by flash chromatography (0-65% MeOH/DCM) gave the product as a brown oil (93 mg, yield)Rate 83%).

[M+H] ⁺ ＝531.3

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- (2-N-morpholinoethyl) phenyl ] methyl ] isoquinoline-1, 5-diamine (93 mg,0.05 mmol) was deprotected using general procedure 12. The crude product was purified via automated prep HPLC (2-60% mass orientation over 20min in alkaline mobile phase). Lyophilization afforded the product as a white solid (6 mg, 30% yield).

[M+H] ⁺ ＝381.2

¹ H NMR(DMSO,400MHz)δ2.36-2.41(4H,m),2.44-2.49(2H,m),2.70(2H,dd,J＝8.8,6.6Hz),3.55(4H,t,J＝4.6Hz),4.44(2H,d,J＝5.8Hz),6.45(1H,d,J＝7.6Hz),6.50(2H,s),6.65(1H,t,J＝6.0Hz),6.96(1H,dd,J＝7.8,1.6Hz),7.08(1H,dd,J＝11.5,1.6Hz),7.14(1H,t,J＝8.0Hz),7.17-7.26(2H,m),7.32(1H,d,J＝8.3Hz),7.74(1H,d,J＝6.1Hz)

Example number 2184

4-chloro-N6- [ [ 2-fluoro-4- [2- (4-methylpiperazin-1-yl) ethyl ] phenyl ] methyl ] isoquinoline-1, 6-diamine

2-fluoro-4- [2- (4-methylpiperazin-1-yl) -2-oxo-ethyl ] benzonitrile

Following general method 8, (4-cyano-3-fluorophenyl) acetic acid (150 mg,0.84 mmol) was coupled with 1-methylpiperazine (0.1 mL,0.92 mmol). By flash chromatography (silica gel, 0-5% (containing 10% NH) ₃ MeOH/DCM) to give the crude product as a brown colorThe product was an oil (48 mg, 22% yield).

[M+H] ⁺ ＝262.1

[ 2-fluoro-4- [2- (4-methylpiperazin-1-yl) ethyl ] phenyl ] methylamine

The overall reduction of the amide and nitrile of 2-fluoro-4- [2- (4-methylpiperazin-1-yl) -2-oxo-ethyl ] benzonitrile (48.0 mg,0.18 mmol) was performed using general method 3 b. The product was isolated as an off-white solid (46.0 mg, 100% yield) and used without further purification.

[M+H] ⁺ ＝252.1

N- [ 4-chloro-6- [ [ 2-fluoro-4- [2- (4-methylpiperazin-1-yl) ethyl ] phenyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

Following general procedure 4, methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (21 mg,0.07 mmol) is reacted with [ 2-fluoro-4- [2- (4-methylpiperazin-1-yl) ethyl ]]Phenyl group]Methylamine (20 mg,0.08 mmol) and NaOtBu (78.mg, 0.24 mmol) in THF (5 mL) were reacted at 40℃for 18h. After concentration in vacuo, the mixture was purified by flash chromatography (0-20% (containing 10% NH) ₃ The residue was purified with MeOH/EtOAc) to give the product as a yellow solid (10 mg, 26% yield).

[M+H] ⁺ ＝486.1

Following general method 14a, N- [ 4-chloro-6- [ [ 2-fluoro-4- [2- (4-methylpiperazin-1-yl) ethyl ] phenyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester (10 mg,0.02 mmol) is deprotected over 24 h. The reaction mixture was concentrated and purified via automated prep HPLC (2-60% mass orientation over 20min in basic mobile phase). Lyophilization afforded the product as a white solid (1 mg, 12% yield).

[M+H] ⁺ ＝428.1

¹ H NMR(CDCl ₃ ,400MHz)δ2.30(3H,s),2.35-2.85(12H,m),4.50(2H,d,J＝5.7Hz),4.56-4.64(1H,m),4.93(2H,s),6.87(1H,dd,J＝9.0,2.4Hz),6.92-7.00(2H,m),7.04(1H,d,J＝2.3Hz),7.30(1H,t,J＝7.7Hz),7.57(1H,d,J＝9.0Hz),7.85(1H,s)

Example number 2212

N5- [ [ 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] -2-oxo-ethyl ] benzonitrile

Following general method 8, (1S, 4S) -2-isopropyl-2, 5-diazabicyclo [2.2.1]Heptane; dihydrochloride (200 mg,0.93 mmol) was coupled with 2- (4-cyano-3-fluorophenyl) acetic acid (185 mg,1.03 mmol). By flash chromatography (silica gel, 0-20% (10% NH) ₃ MeOH)/DCM) to give the product as a pale brown gum (225 mg, 80% yield).

[M+H] ⁺ ＝302.1

¹ H NMR(400MHz,CDCl ₃ ) Delta 1.04-1.07 (6H, m), 1.67-1.99 (2H, m), 2.33-2.65 (2H, m), 3.04-3.43 (2H, m), 3.57-3.80 (4H, m), 4.29 and 4.72 (1H, s), 7.18-7.23 (2H, m), 7.55-7.61 (1H, m)

[ 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methylamine

The overall reduction of 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] -2-oxo-ethyl ] benzonitrile (225 mg,0.75 mmol) of nitrile and amide was performed using general method 3b at rt and stirred for 13h. The product was isolated as a yellow oil (175 mg,0.60mmol, 80% yield) and used without further purification.

[M+H] ⁺ ＝292.1

N1- [ (2, 4-Dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

Following general procedure 4, [ 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1]]Hept-2-yl]Ethyl group]Phenyl group]Methylamine (71 mg,0.24 mmol) and 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (91 mg,0.24 mmol) and Cs-containing ₂ CO ₃ (176 mg,0.54 mmol) of 1, 4-dioxane (3 mL) was reacted at 60℃for 5 days. The reaction mixture was cooled, byFiltration and washing with EtOAc (80 mL) and MeOH (3 mL) gave the crude product as a brown oil (108 mg, 76% yield) which was used without purification.

[M+H] ⁺ ＝584.1

N1- [ (2, 4-Dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- [ (1S, 4S) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine (108 mg,0.19 mmol) was deprotected using general procedure 12. The crude product was purified via automated prep HPLC (2-60% mass orientation over 20min in alkaline mobile phase). Lyophilization afforded the product as a white solid (5 mg, 6% yield).

[M+H] ⁺ ＝434.2

¹ H NMR(DMSO-d6,400MHz)δ0.93(6H,dd,J＝14.9,6.1Hz),1.50(2H,q,J＝9.0Hz),2.40(1H,d,J＝9.4Hz),2.52-2.65(6H,m),2.65-2.74(2H,m),3.20(2H,s),4.44(2H,d,J＝5.8Hz),6.45(1H,d,J＝7.7Hz),6.49(2H,s),6.65(1H,t,J＝6.0Hz),6.95(1H,dd,J＝7.8,1.6Hz),7.07(1H,dd,J＝11.5,1.6Hz),7.13(1H,t,J＝8.0Hz),7.17-7.24(2H,m),7.32(1H,d,J＝8.3Hz),7.74(1H,d,J＝6.1Hz)

Example number 2213

N5- [ [ 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

Tert-butyl- (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid ester

To (1R, 4R) -2, 5-diazabicyclo [2.2.1]To a solution of tert-butyl heptane-2-carboxylate (500 mg,2.52 mmol) in THF (10 mL) was added acetone (1.0 mL,13.62 mmol) and the reaction stirred for 15min before sodium triacetoxyborohydride (1.6 g,7.57 mmol) was added. The reaction mixture was stirred at rt for 18h, then with DCM (50 mL) and NaHCO ₃ (saturated aqueous solution 15 mL) was diluted. The aqueous layer was re-extracted with DCM (2X 20 mL). The combined organics were treated with additional NaHCO ₃ (saturated aqueous solution 15 mL), washing and drying (MgSO) ₄ ) Filtration and concentration gave the product as a colourless oil (604 mg, 100% yield).

[M+H] ⁺ ＝241.1

¹ H NMR(CDCl ₃ ,400MHz)δ0.98-1.13(6H,m),1.45(9H,s),1.65-1.75(1H,m),1.81-1.87(1H,m),2.45(1H,dd,J＝52.7,9.6Hz),2.55-2.70(1H,m),3.01-3.17(2H,m),3.52(1H,dd,J＝34.8,10.3Hz),3.68(1H,s),4.26(1H,d,J＝47.9Hz)ppm。

2-isopropyl-2, 5-diazabicyclo [2.2.1] heptane; dihydrochloride salt

Boc deprotection of tert-butyl (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (604 mg,2.51 mmol) was performed using general method 7 a. The reaction mixture was concentrated to give the product as a white solid (601 mg, quantitative yield).

[M+H] ⁺ ＝141.0

2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] -2-oxo-ethyl ] benzonitrile

(1R, 4R) -2-isopropyl-2, 5-diazabicyclo [2.2.1 using general procedure 8]Heptane; dihydrochloride (325 mg,1.52 mmol) was coupled with 2- (4-cyano-3-fluorophenyl) acetic acid (301 mg,1.68 mmol). By flash chromatography (silica gel, 0-10% (containing 10% NH) ₃ MeOH)/DCM) to give the product as a colorless oil (267 mg, 58% yield).

[M+H] ⁺ ＝302.1

[ 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methylamine

The overall reduction of amide and nitrile 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] -2-oxo-ethyl ] benzonitrile (218 mg,0.72 mmol) was performed using general method 3b for 13h. The product was isolated as a yellow oil (186 mg, 88% yield) and used without further purification.

[M+H] ⁺ ＝292.1

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine

Following general procedure 4, [ 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1]]Hept-2-yl]Ethyl group]Phenyl group]Methylamine (71 mg,0.24 mmol) and 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (91 mg,0.24 mmol) and Cs-containing ₂ CO ₃ (176 mg,0.54 mmol) of 1, 4-dioxane (3 mL) was reacted at 60℃for 18h. Quenching and passing throughAfter filtration, the product was obtained as a brown oil (271 mg, 100% yield) and used directly.

[M+H] ⁺ ＝584.3

Following general method 12, N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [ 2-fluoro-4- [2- [ (1R, 4R) -5-isopropyl-2, 5-diazabicyclo [2.2.1] hept-2-yl ] ethyl ] phenyl ] methyl ] isoquinoline-1, 5-diamine (142 mg,0.24 mmol) was deprotected. The crude material was purified via automated prep HPLC (2-60% mass orientation in the acidic mobile phase for 20 min) to give the product as a brown solid (22 mg, 17% yield).

[M+H] ⁺ ＝434.2

¹ H NMR(DMSO,400MHz)δ1.06(6H,dd,J＝21.2,6.2Hz),1.72(2H,q,J＝10.2Hz),2.62-2.98(9H,m),3.44(1H,s),3.80(1H,s),4.45(2H,d,J＝5.7Hz),6.45(1H,d,J＝7.7Hz),6.61(2H,s),6.68(1H,t,J＝6.0Hz),6.97(1H,dd,J＝7.9,1.6Hz),7.06-7.27(4H,m),7.33(1H,d,J＝8.4Hz),7.74(1H,d,J＝6.1Hz),8.25(2H,s)

Example No. 1041

4-chloro-N6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -3-pyridinyl ] methyl ] isoquinoline-1, 6-diamine

6- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-6-yl) methoxy) nicotinonitrile

Following general procedure 1b, (5, 6,7, 8-tetrahydroimidazo [1,2-a]Pyridin-6-yl) methanol (650 mg,4.27 mmol) was reacted with 6-fluoronicotinonitrile (626 mg,5.12 mmol) for 18h. The solids were removed by filtration and the filtrate was concentrated. By flash chromatography (silica gel, 1-5% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as an orange solid (676 mg, 59% yield).

[M+H] ⁺ ＝255.1

¹ H NMR(500MHz,DMSO-d6)1.62-1.77(1H,m),2.02-2.12(1H,m),2.45-2.50(1H,m),2.66-2.76(1H,m),2.79-2.90(1H,m),3.69-3.80(1H,m),4.18(1H,dd,J＝12.4,5.2Hz),4.35(1H,dd,J＝10.7,7.3Hz),4.45(1H,dd,J＝10.7,6.0Hz),6.79-6.83(1H,m),6.97-7.02(1H,m),7.03-7.08(1H,m),8.15-8.21(1H,m),8.68-8.73(1H,m)

[6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -3-pyridinyl ] methylamine

Following general method 3a, the reduction of nitrile 6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyridine-3-carbonitrile (140 mg,0.55 mmol) was performed using raney nickel over 30 min. The solvent was removed in vacuo to give the product as a colourless oil (138 mg, 97% yield).

[M+H] ⁺ ＝259.1

¹ H NMR(CDCl ₃ ,400MHz)δ1.73-1.85(1H,m),2.10-2.22(1H,m),2.50-2.63(1H,m),2.78-2.92(1H,m),2.98-3.11(1H,m),3.71-3.79(1H,m),3.81(2H,s),4.20(1H,dd,J＝12.2,5.2Hz),4.24-4.30(1H,m),4.39-4.45(1H,m),6.73(1H,d,J＝8.4Hz),6.76-6.81(1H,m),6.98(1H,d,J＝1.3Hz),7.59(1H,dd,J＝8.5,2.6Hz),8.05(1H,d,J＝2.5Hz)

N- [ 4-chloro-6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -3-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

/>

Following general procedure 4, [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-ylmethoxy) -3-pyridinyl]Methylamine (135 mg,0.47 mmol) was reacted with methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (147 mg,0.47 mmol) and THF (5 mL) containing NaOtBu (305 mg,0.93 mmol) at 40℃for 1h. The mixture was cooled to rt, quenched with AcOH (53 μl,0.93 mmol) and concentrated. By flash chromatography (silica gel, 0-80% (containing 2% NH) ₄ The residue was purified with EtOAc/EtOH (3:1))/petroleum ether 60-80 to give the product as a pale yellow oil (219 mg, 96% yield).

[M+H] ⁺ ＝493.1

N- [ 4-chloro-6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] according to general procedure 14a over 72h]Pyridin-7-ylmethoxy) -3-pyridinyl]Methylamino group]-1-isoquinolinyl]Deprotection of methyl carbamate (219 mg,0.44 mmol). The reaction was cooled to rt, quenched with AcOH (0.1 mL,2.0 mmol) and purified by SCX in 7M NH ₃ Eluting in MeOH. The product was isolated as a white solid after lyophilization (98 mg, 51% yield).

[M+H] ⁺ ＝435.1

¹ H NMR(DMSO-d6,400MHz)δ1.59-1.73(1H,m),1.96-2.12(1H,m),2.45(1H,br s),2.64-2.77(1H,m),2.77-2.88(1H,m),3.72(1H,dd,J＝12.3,10.1Hz),4.16(1H,dd,J＝12.3,5.2Hz),4.22(1H,dd,J＝10.7,7.4Hz),4.32(1H,d,J＝6.0Hz),4.34(2H,d,J＝5.6Hz),6.55(2H,s),6.71(1H,d,J＝2.3Hz),6.79(1H,d,J＝1.2Hz),6.82-6.86(1H,m),6.95(1H,dd,J＝9.1,2.4Hz),6.97-7.02(1H,m),7.06(1H,t,J＝5.8Hz),7.65(1H,s),7.74(1H,dd,J＝8.5,2.5Hz),7.92(1H,d,J＝9.0Hz),8.20(1H,d,J＝2.4Hz)

Example No. 4298

N5- ((2- ((5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine

Following general procedure 4, (2- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-yl) methoxy) pyridin-4-yl methylamine (108 mg,0.42 mmol) was reacted with 5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine (156 mg,0.42 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (80 mg,0.84 mmol) at 60℃for 1h. The reaction mixture was cooled to rt and concentrated, after which it was purified by flash evaporationFlash chromatography (silica gel, 0-80% (containing 2% NH) ₃ EtOAc/EtOH (3:1))/petroleum ether) to give the product as a yellow oil (85 mg,0.13mmol, 32% yield).

[M+H] ⁺ ＝551.2

N1- (2, 4-Dimethoxybenzyl) -N5- ((2- ((5, 6,7, 8-tetrahydroimidazo [1, 2-a) using general procedure 12]Pyridin-7-yl) methoxy) pyridin-4-yl) methyl) isoquinoline-1, 5-diamine (200 mg,0.36 mmol). By flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ EtOAc/MeCN/EtOH (3:3:1))/petroleum ether) followed by automated prep HPLC (2-60% mass orientation over 20min in basic mobile phase). Lyophilization afforded the product as a white solid (30 mg, 21% yield).

[M+H] ⁺ ＝401.2

¹ H NMR(DMSO-d6,400MHz)δ1.57-1.77(1H,m),2.05-2.15(1H,m),2.26-2.40(1H,m),2.41-2.47(1H,m),2.89(1H,ddd,J＝16.2,5.0,1.4Hz),3.85(1H,td,J＝11.9,4.7Hz),4.00-4.09(1H,m),4.22(2H,dd,J＝6.6,1.6Hz),4.45(2H,d,J＝5.9Hz),6.38(1H,dd,J＝7.8,0.9Hz),6.51(2H,s),6.76-6.78(1H,m),6.78(1H,d,J＝1.2Hz),6.81(1H,t,J＝6.1Hz),6.97(1H,d,J＝1.2Hz),6.98(1H,dd,J＝5.3,1.4Hz),7.12(1H,t,J＝8.0Hz),7.20(1H,dd,J＝6.3,0.9Hz),7.33(1H,d,J＝8.3Hz),7.76(1H,d,J＝6.1Hz),8.06(1H,dd,J＝5.3,0.7Hz)ppm。

Example No. 4299

N5- [ [2- [ (1-isopropyl-4-piperidinyl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

4- [ (4-cyano-2-pyridinyl) oxymethyl ] piperidine-1-carboxylic acid tert-butyl ester

Following general method 1b, N-boc-4- (hydroxymethyl) piperidine (3523 mg,1.64 mmol) was reacted with MeCN (4 mL) containing 4-cyano-2-fluoropyridine (200 mg,1.64 mmol) at 50℃for 18h. The reaction mixture was cooled to rt and diluted with water (10 mL). The product was extracted into DCM (2X 25 mL) and dried (MgSO ₄ ) Filtering and concentrating. The residue was purified by flash chromatography (silica gel, 5-100% EtOAc/petroleum ether 60-80) to give the product as a pale yellow oil (500 mg, 96% yield).

[M-boc+H] ⁺ ＝218.1

¹ H NMR(400MHz,CDCl ₃ )δ1.21-1.32(2H,m),1.47(9H,s),1.80(2H,d,J＝12.9Hz),1.92-2.02(1H,m),2.75(2H,t,J＝11.8Hz),4.09-4.20(4H,m),6.99(1H,d,J＝0.9Hz),7.07(1H,dd,J＝5.1,1.3Hz),8.28(1H,d,J＝5.0Hz)

4- [ [4- (aminomethyl) -2-pyridinyl ] oxymethyl ] piperidine-1-carboxylic acid tert-butyl ester

According to general procedure 3a, nitrile 4- [ (4-cyano-2-pyridinyl) oxymethyl ] piperidine-1-carboxylic acid tert-butyl ester (500 mg,1.58 mmol) is reduced using Raney nickel for 1h. The solvent was removed in vacuo to give the product as a colourless oil (497 mg, 98% yield).

[M+H] ⁺ ＝322.1

¹ H NMR(CDCl ₃ ,400MHz)δ1.25(2H,qd,J＝12.4,4.4Hz),1.46(9H,s),1.73-1.83(2H,m),1.89-2.00(1H,m),2.33(2H,br s),2.73(2H,t,J＝12.8Hz),3.86(2H,s),4.04-4.19(4H,m),6.65-6.75(1H,m),6.77-6.88(1H,m),8.07(1H,dd,J＝5.3,0.7Hz)

4- [ [4- [ [ [1- [ (2, 4-Dimethoxyphenyl) methylamino ] -5-isoquinolinyl ] amino ] methyl ] -2-pyridinyl ] oxymethyl ] piperidine-1-carboxylic acid tert-butyl ester

Using general procedure 4, 4- [ [4- (aminomethyl) -2-pyridinyl]Oxymethyl group]Piperidine-1-carboxylic acid tert-butyl ester (497 mg,1.55 mmol) and 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (635 mg,1.7 mmol) and Cs-containing ₂ CO ₃ (1014 mg,3.09 mmol) of 1, 4-dioxane (6 mL) was reacted at 60℃for 18h. Quenching and passing throughAfter filtration, the crude product was purified by flash chromatography (silica gel, 10-100% EtOAc/petroleum ether 60-80) to give the product as a pale yellow gum (800 mg, 84% yield).

[M+H] ⁺ ＝614.3

¹ H NMR(400MHz,CDCl ₃ )δ0.83-0.97(2H,m),1.45(9H,s),1.59(3H,s),1.77-1.99(3H,m),2.72(2H,t,J＝12.3Hz),3.80(3H,s),3.86(3H,s),4.47(2H,d,J＝5.5Hz),4.72-4.78(3H,m),5.63(1H,t,J＝5.3Hz),6.44-6.55(3H,m),6.75(1H,s),6.85-6.90(2H,m),7.08(1H,d,J＝8.4Hz),7.20-7.32(3H,m),8.05(1H,d,J＝6.1Hz),8.09(1H,d,J＝5.4Hz)

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- (4-piperidinylmethoxy) -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

4- [ [4- [ [ [1- [ (2, 4-dimethoxyphenyl) methylamino ] using general procedure 7b]-5-isoquinolinyl ]Amino group]Methyl group]-2-pyridyl group]Oxymethyl group]Boc deprotection of tert-butyl piperidine-1-carboxylate (800 mg,1.3 mmol). The reaction mixture was concentrated, converted to free base using bicarbonate cartridge and quenched with Et ₂ O (20 mL) was triturated to give the product as an orange oil (708 mg, 97% yield).

[M+H] ⁺ ＝514.2

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- [ (1-isopropyl-4-piperidinyl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

Following general method 9, N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- (4-piperidinylmethoxy) -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine (75 mg,0.15 mmol) was reacted with THF (5 mL) containing acetone (54 μl,0.73 mmol). The crude product was purified by flash chromatography (silica gel, 0-30% meoh/DCM) to give the product as a pale yellow gum (55 mg, 68% yield).

[M+H] ⁺ ＝556.4

Deprotection of N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- [ (1-isopropyl-4-piperidinyl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine (63 mg,0.11 mmol) was carried out according to general method 12. The crude product was purified via automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (27 mg, 59% yield).

[M+H] ⁺ ＝406.3

¹ H NMR(DMSO,400MHz)δ0.93(6H,d,J＝6.6Hz),1.13-1.23(2H,m),1.59-1.68(3H,m),2.02-2.08(2H,m),2.60-2.67(1H,m),2.74(2H,d,J＝11.7Hz),4.02(2H,d,J＝6.2Hz),4.43(2H,d,J＝5.9Hz),6.37(1H,d,J＝7.7Hz),6.51(2H,s),6.71(1H,s),6.79(1H,t,J＝6.1Hz),6.95(1H,dd,J＝5.4,0.8Hz),7.11(1H,t,J＝7.9Hz),7.19(1H,d,J＝6.2Hz),7.33(1H,d,J＝8.3Hz),7.76(1H,d,J＝6.0Hz),8.03(1H,d,J＝5.3Hz)

Example number 4300

4-chloro-N6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -4-pyridinyl ] methyl ] isoquinoline-1, 6-diamine

N- [ 4-chloro-6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -4-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

Following general procedure 4, [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-ylmethoxy) -4-pyridinyl]Methylamine (108 mg,0.42 mmol) was reacted with methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (132 mg,0.42 mmol) and THF (6 mL) containing NaOtBu (121 mg,1.25 mmol) at rt for 45min. The mixture was concentrated and purified by flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ EtOAc/MeCN/EtOH (3:3:1))/petroleum ether 60-80) to give the product as a pale orange oil (83 mg, 38% yield).

[M+H] ⁺ ＝493.1

N- [ 4-chloro-6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] following general procedure 14a]Pyridin-7-ylmethoxy) -4-pyridinyl]Methylamino group]-1-isoquinolinyl]Deprotection of methyl carbamate (84 mg,0.16 mmol) was continued for 18h. The reaction was cooled to rt and concentrated. By flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ EtOAc/MeCN/EtOH (3:3:1))/petroleum ether 60-80) followed by automated prep HPLC (2-60% mass orientation over 20min in alkaline mobile phase). Lyophilization afforded the product as a white solid (25 mg, 37% yield).

[M+H] ⁺ ＝435.1

¹ H NMR(DMSO-d6,400MHz)δ1.61-1.77(1H,m),2.01-2.18(1H,m),2.27-2.40(1H,m),2.43-2.48(1H,m),2.90(1H,dd,J＝16.2,4.9Hz),3.86(1H,td,J＝12.0,4.8Hz),4.06(1H,ddd,J＝12.5,5.5,2.8Hz),4.24(2H,d,J＝6.5Hz),4.42(2H,d,J＝6.1Hz),6.57(2H,s),6.65(1H,d,J＝2.3Hz),6.79(1H,d,J＝1.3Hz),6.82(1H,s),6.95(1H,dd,J＝9.1,2.4Hz),6.97(1H,d,J＝1.2Hz),7.00(1H,dd,J＝5.3,1.4Hz),7.21(1H,t,J＝6.1Hz),7.64(1H,s),7.94(1H,d,J＝9.1Hz),8.09(1H,dd,J＝5.3,0.7Hz)

Example number 4301

4- [ [4- [ [ (1-amino-5-isoquinolinyl) amino ] methyl ] -2-pyridinyl ] oxymethyl ] -1-methyl-pyridin-2-one

2- [ (1-methyl-2-oxo-4-pyridinyl) methoxy ] pyridine-4-carbonitrile

Following general method 1b, 4- (hydroxymethyl) -1-methylpyridin-2 (1H) -one (100 mg,0.72 mmol) was reacted with 4-cyano-2-fluoropyridine (88 mg,0.72 mmol) at 60℃for 7 days. The reaction mixture was cooled to rt, diluted with water (25 mL), and the product was extracted with DCM (3×20 mL). The combined organics were washed with brine (20 mL) and filtered through phase separation paper and concentrated. The crude product was purified by flash chromatography (silica gel, 0-20% MeOH/DCM) to give the product (56 mg, 32% yield).

[M+H] ⁺ ＝242.0

¹ H NMR(CDCl ₃ ,400MHz)δ3.54(3H,s),5.26(2H,d,J＝1.1Hz),6.18(1H,dd,J＝6.9,1.9Hz),6.59(1H,q,J＝1.4Hz),7.09(1H,t,J＝1.1Hz),7.12(1H,dd,J＝5.2,1.3Hz),7.28(1H,d,J＝7.0Hz),8.28(1H,dd,J＝5.2,0.9Hz)

4- [ [4- (aminomethyl) -2-pyridinyl ] oxymethyl ] -1-methyl-pyridin-2-one

The reduction of nitrile 2- [ (1-methyl-2-oxo-4-pyridinyl) methoxy ] pyridine-4-carbonitrile (56 mg,0.23 mmol) was performed using Raney nickel over 15min using general method 3 a. The solvent was removed in vacuo to give the product as a colourless oil (56 mg, 98% yield).

[M+H] ⁺ ＝246.0

4- [ [4- [ [ [1- [ (2, 4-dimethoxyphenyl) methylamino ] -5-isoquinolinyl ] amino ] methyl ] -2-pyridinyl ] oxymethyl ] -1-methyl-pyridin-2-one

Following general procedure 4, 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (87 mg,0.23 mmol) and 4- [ [4- (aminomethyl) -2-pyridinyl)]Oxymethyl group]-1-methyl-pyridin-2-one (57 mg,0.23 mmol), cs-containing ₂ CO ₃ (152 mg,0.46 mmol) of 1, 4-dioxane (5 mL) was reacted at 60℃for 20h. Quenching and passing throughAfter filtration, the residue was purified by flash chromatography (silica gel, 20-100% EtOAc/petroleum ether followed by 0-20% MeOH/EtOAc) to give the product as an orange glass (102 mg, 82% yield).

[M+H] ⁺ ＝538.2

Deprotection of 4- [ [4- [ [ [1- [ (2, 4-dimethoxyphenyl) methylamino ] -5-isoquinolinyl ] amino ] methyl ] -2-pyridinyl ] oxymethyl ] -1-methyl-pyridin-2-one (102 mg,0.19 mmol) was performed using general method 12. The product was purified via automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (25 mg, 34% yield).

[M+H] ⁺ ＝388.2

¹ H NMR(DMSO,400MHz)δ3.37(3H,s),4.47(2H,d,J＝6.0Hz),5.17(2H,d,J＝1.2Hz),6.18(1H,dd,J＝6.9,1.9Hz),6.29(1H,d,J＝1.7Hz),6.40(1H,d,J＝7.7Hz),6.52(2H,s),6.82(1H,t,J＝6.1Hz),6.87(1H,s),7.01(1H,dd,J＝5.3,1.4Hz),7.12(1H,t,J＝8.0Hz),7.20(1H,d,J＝6.1Hz),7.34(1H,d,J＝8.3Hz),7.62(1H,d,J＝7.0Hz),7.77(1H,d,J＝6.0Hz),8.05(1H,d,J＝5.4Hz)

Example No. 1044

4-chloro-N6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamino) -3-pyridinyl ] methyl ] isoquinoline-1, 6-diamine

6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamino) pyridine-3-carbonitrile

Following general method 1d, 5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamine (100 mg,0.66 mmol) is reacted with 5-cyano-2-fluoropyridine (81 mg,0.66 mmol) at 90℃for 90min. The crude material was purified by flash chromatography (silica gel, 0-20% MeOH/DCM) to give the product as an off-white solid (100 mg, 60% yield).

[M+H] ⁺ ＝254.1

5- (aminomethyl) -N- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethyl) pyridin-2-amine

The reduction of nitrile 6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamino) pyridine-3-carbonitrile (165 mg,0.65 mmol) was performed using Raney nickel using general method 3a over 45 min. The solvent was removed in vacuo to give the product as a yellow oil (147 mg, 88% yield).

[M+H] ⁺ ＝258.1

N- [ 4-chloro-6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamino) -3-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

Following general procedure 4, 5- (aminomethyl) -N- (5, 6,7, 8-tetrahydroimidazo [1, 2-a)]Pyridin-7-ylmethyl) pyridin-2-amine (147 mg,0.57 mmol) was reacted with methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (180 mg,0.57 mmol) and THF (5 mL) containing NaOtBu (110 mg,1.14 mmol) at 40℃for 5h. Quenching and passing through After filtration, the mixture was purified by flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ The residue was purified with EtOAc/MeCN/EtOH (3:3:1))/petroleum ether 60-80 to give the product as a pale yellow gum (133 mg, 47% yield).

[M+H] ⁺ ＝492.2

Deprotection of methyl N- [ 4-chloro-6- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethylamino) -3-pyridinyl ] methylamino ] -1-isoquinolinyl ] carbamate (133 mg,0.27 mmol) was performed over 24h using general method 14. The reaction was cooled and concentrated. The residue was purified by automated prep HPLC (2-60% mass orientation in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (40 mg, 34% yield).

[M+H] ⁺ ＝434.1

¹ H NMR(DMSO,400MHz)δ1.54-1.69(1H,m),2.05(1H,d,J＝13.5Hz),2.11-2.19(1H,m),2.37(1H,dd,J＝16.4,10.6Hz),2.88(1H,dd,J＝16.4,5.1,1.5Hz),3.22-3.31(2H,m),3.81(1H,td,J＝12.3,11.8,4.7Hz),4.00-4.10(1H,m),4.17(2H,d,J＝5.4Hz),6.50(1H,d,J＝8.5,0.7Hz),6.54(2H,s),6.67(1H,t,J＝5.8Hz),6.71(1H,d,J＝2.3Hz),6.78(1H,d,J＝1.2Hz),6.86-6.98(3H,m),7.41(1H,dd,J＝8.6,2.4Hz),7.65(1H,s),7.90(1H,d,J＝9.1Hz),8.01(1H,d,J＝2.3Hz)

Example number 1131

2- [ (3S) -1- [5- [ [ (1-amino-5-isoquinolinyl) amino ] methyl ] -2-pyridinyl ] pyrrolidin-3-yl ] propan-2-ol

(S) -6- (3- (2-hydroxy-prop-2-yl) pyrrolidin-1-yl) nicotinonitrile

Following general method 1d, (S) -2- (3-pyrrolidinyl) -2-propanol (106 mg,0.82 mmol) was reacted with 5-cyano-2-fluoropyridine (100 mg,0.82 mmol) at 120 ℃ under microwave irradiation for 60min. The product (199 mg, 98% yield) was isolated and used without further purification.

[M+H] ⁺ ＝232.1

¹ H NMR(CDCl ₃ ,400MHz)δ1.31(3H,s),1.31(3H,s),1.37(1H,s),1.97(1H,d,J＝12.8Hz),2.05-2.16(1H,m),2.39(1H,q,J＝9.0Hz),3.40(2H,dt,J＝20.8,10.2Hz),3.69(2H,s),6.34(1H,dd,J＝8.9,0.8Hz),7.57(1H,dd,J＝8.9,2.3Hz),8.40(1H,dd,J＝2.3,0.8Hz)

2- [ (3S) -1- [5- (aminomethyl) -2-pyridinyl ] pyrrolidin-3-yl ] propan-2-ol

Nitrile (S) -6- (3- (2-hydroxypropan-2-yl) pyrrolidin-1-yl) nicotinonitrile (199mg, 0.81 mmol) was reduced over 30min using Raney nickel according to general method 3 a. The solvent was removed in vacuo to give the product as a colourless oil (190 mg, quantitative yield).

[M+H] ⁺ ＝236.1

2- [ (3S) -1- [5- [ [ [1- [ (2, 4-dimethoxyphenyl) methylamino ] -5-isoquinolinyl ] amino ] methyl ] -2-pyridinyl ] pyrrolidin-3-yl ] propan-2-ol

Using general procedure 4, 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (151 mg,0.4 mmol) and 2- [ (3S) -1- [5- (aminomethyl) -2-pyridinyl]Pyrrolidin-3-yl]Propan-2-ol (95 mg,0.4 mmol) and Cs-containing ₂ CO ₃ (265 mg,0.81 mmol) of 1, 4-dioxane (5 mL) was reacted at 60℃for 20h. Quenching and passing throughAfter filtration, the crude product was purified by flash chromatography (silica gel, 0-20% meoh/EtOAc) to give the product as a colorless glass (73 mg, 34% yield).

[M+H] ⁺ ＝528.3

Deprotection of 2- [ (3S) -1- [5- [ [ [1- [ (2, 4-dimethoxyphenyl) methylamino ] -5-isoquinolinyl ] amino ] methyl ] -2-pyridinyl ] pyrrolidin-3-yl ] propan-2-ol (73 mg,0.14 mmol) was performed using general method 12. The product was purified via automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (17 mg, 33% yield).

[M+H] ⁺ ＝378.3

¹ H NMR(DMSO,400MHz)δ1.11(3H,s),1.12(3H,s),1.75-1.94(3H,m),2.24(1H,p,J＝8.7Hz),3.13-3.26(2H,m),3.50(2H,td,J＝8.8,8.2,4.7Hz),4.28(2H,d,J＝5.7Hz),6.36(1H,d,J＝8.6Hz),6.49(2H,s),6.53(1H,s),6.56(1H,q,J＝4.9,4.0Hz),7.12(1H,d,J＝8.0Hz),7.16(1H,d,J＝5.8Hz),7.30(1H,d,J＝8.3Hz),7.48(1H,dd,J＝8.6,2.4Hz),7.72(1H,d,J＝6.1Hz),8.08(1H,d,J＝2.3Hz)

Example number 1052

4-chloro-N6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidin-5-yl ] methyl ] isoquinoline-1, 6-diamine

2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidine-5-carbonitrile

Following general method 1a, 5,6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethanol (200 mg,1.31 mmol) is reacted with THF containing 2-chloro-5-pyrimidine carbonitrile (183 mg,1.31 mmol) for 18h. The crude product was purified by flash chromatography (silica gel, 0-20% MeOH/DCM) to give the product as a brown solid (90 mg, 27% yield).

[M+H] ⁺ ＝256.0

[2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidin-5-yl ] methylamine

The reduction of nitrile 2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidine-5-carbonitrile (90 mg,0.35 mmol) was performed using Raney nickel using general method 3a over 15 min. The solvent was removed in vacuo to give the product as a yellow oil (100 mg, quantitative yield).

[M+H] ⁺ ＝260.1

N- [ 4-chloro-6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidin-5-yl ] methylamino ] -1-isoquinolinyl ] carbamic acid methyl ester

Using general procedure 4, [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-ylmethoxy) pyrimidin-5-yl]Methylamine (100 mg,0.39 mmol) was reacted with methyl N- (6-bromo-4-chloro-1-isoquinolinyl) carbamate (122 mg,0.39 mmol) and THF (5 mL) containing NaOtBu (111 mg,1.16 mmol) at 40℃for 1h. The mixture was concentrated and purified by flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ EtOAc/MeCN/EtOH (3:3:1))/petroleum ether 60-80) to give the product as a pale orange oil (91 mg, 37% yield).

[M+H] ⁺ ＝494.2

Deprotection of methyl N- [ 4-chloro-6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidin-5-yl ] methylamino ] -1-isoquinolinyl ] carbamate (91 mg,0.18 mmol) was performed at 60℃for 4 days using general procedure 14 b. The crude product was purified via automated prep HPLC (2-60% mass orientation over 20min in basic mobile phase) and lyophilized to give the product as a white solid (8 mg, 10% yield).

[M+H] ⁺ ＝436.1

¹ H NMR(DMSO-d6,400MHz)δ1.65-1.81(1H,m),2.05-2.19(1H,m),2.33-2.44(1H,m),2.86-2.97(1H,m),3.88(1H,td,J＝11.9,4.7Hz),4.02-4.14(1H,m),4.30(2H,dd,J＝6.5,1.5Hz),4.37(2H,d,J＝5.6Hz),6.58(2H,br s),6.73(1H,d,J＝2.3Hz),6.80(1H,d,J＝1.3Hz),6.96(1H,dd,J＝9.1,2.4Hz),6.98(1H,d,J＝1.3Hz),7.04(1H,t,J＝5.7Hz),7.67(1H,s),7.94(1H,d,J＝9.0Hz),8.65(2H,s)

Example number 4320

N5- [ [2- [ (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

2- [ (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] pyridine-4-carbonitrile

Following general procedure 1d, (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a]Pyridin-7-yl) methanol (130 mg,0.78 mmol) was reacted with 4-cyano-2-fluoropyridine (105 mg,0.86 mmol) at 60℃for 18h. The reaction mixture was cooled to rt and diluted with water (5 mL). The crude product was extracted into EtOAc (3X 20 mL) and dried (MgSO ₄ ) Filtering and concentrating. The crude product was purified by flash chromatography (silica gel, 0-20% MeOH/DCM) to give the product as a brown oil (93 mg, 44% yield).

[M+H] ⁺ ＝269.0

[2- [ (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methylamine

According to general procedure 3a, nitrile 2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) pyrimidine-5-carbonitrile (176 mg,0.69 mmol) is reduced using Raney nickel over 30 min. The solvent was removed in vacuo to give the product as a yellow oil (91 mg, 96% yield).

[M+H] ⁺ ＝273.1

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

Following general procedure 4, 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (125 mg,0.33 mmol) and [2- [ (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-yl) methoxy]-4-pyridinyl]Methylamine (91 mg,0.33 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (75 mg,0.67 mmol) were reacted at 60℃for 1h. Quenching and passing throughAfter filtration, the mixture was purified by flash chromatography (silica gel, 0-20% (containing 10% NH) ₄ OH in MeOH)/DCM) to give the product as an orange solid (111 mg, 59% yield).

[M+H] ⁺ ＝565.3

Deprotection of N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- [ (3-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine (111 mg,0.2 mmol) was performed using general method 12. Purification via automated preparative HPLC (mass directed 2-60% over 20min in the basic mobile phase) and lyophilization of the product afforded the product as an off-white solid (31 mg, 38% yield).

[M+H] ⁺ ＝415.2

¹ H NMR(DMSO,400MHz)δ1.60-1.78(1H,m),2.08(3H,s),2.09-2.19(1H,m),2.21-2.34(1H,m),2.43(1H,dd,J＝16.1,10.8Hz),2.84(1H,dd,J＝16.1,4.9,1.5Hz),3.66(1H,td,J＝11.8,4.9Hz),3.85-3.95(1H,m),4.15-4.27(2H,m),4.45(2H,d,J＝5.9Hz),6.38(1H,d,J＝7.6Hz),6.50(1H,d,J＝1.2Hz),6.54(2H,s),6.74-6.80(1H,m),6.83(1H,t,J＝6.1Hz),6.98(1H,dd,J＝5.3,1.4Hz),7.12(1H,t,J＝8.0Hz),7.20(1H,d,J＝6.1Hz),7.33(1H,d,J＝8.3Hz),7.77(1H,d,J＝6.0Hz),8.06(1H,d,J＝5.3Hz)

Example number 4429

N6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -4-pyridinyl ] methyl ] -2, 7-naphthyridine-1, 6-diamine

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -4-pyridinyl ] methyl ] -2, 7-naphthyridine-1, 6-diamine

Following general procedure 4, 6-chloro-N- [ (2, 4-dimethoxyphenyl) methyl]-2, 7-naphthyridin-1-amine (127 mg,0.38 mmol) with [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-ylmethoxy) -4-pyridinyl]Methylamine (68 mg,0.26 mmol) and Cs-containing ₂ CO ₃ (216 mg,0.66 mmol) of THF (3 mL) was reacted at 60℃for 48h. The reaction mixture was cooled to rt and concentrated, after which it was purified by flash chromatography (silica gel, 0-100% (containing 2% NH) ₃ EtOAc/EtOH (3:3:1))/petroleum ether) to give the product as a pale yellow oil (120 mg, 82% yield).

[M+H] ⁺ ＝552.3

Deprotection of N1- [ (2, 4-dimethoxyphenyl) methyl ] -N6- [ [2- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-ylmethoxy) -4-pyridinyl ] methyl ] -2, 7-naphthyridine-1, 6-diamine (120 mg,0.22 mmol) was performed over 3h following general method 12. The crude product was purified via automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (22 mg, 26% yield).

[M+H] ⁺ ＝402.2

¹ H NMR(DMSO-d ₆ ,400MHz)δ1.62-1.79(1H,m),2.10(1H,d,J＝13.8Hz),2.27-2.41(1H,m),2.42-2.48(1H,m),2.90(1H,dd,J＝16.2,4.8Hz),3.85(1H,dt,J＝12.0,5.8Hz),4.00-4.11(1H,m),4.23(2H,d,J＝6.5Hz),4.50(2H,d,J＝6.3Hz),6.33(1H,s),6.47(1H,d,J＝5.8Hz),6.75(1H,s),6.79(1H,d,J＝1.3Hz),6.82(2H,s),6.95(1H,dd,J＝5.3,1.4Hz),6.97(1H,d,J＝1.3Hz),7.36(1H,t,J＝6.3Hz),7.62(1H,d,J＝5.9Hz),8.05(1H,d,J＝5.2Hz),9.05(1H,s)ppm。

Example No. 1049

N5- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) -3-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) pyridine-3-carbonitrile

Following general procedure 1b, 5,6,7, 8-tetrahydroimidazo [1,2-a]Pyridin-7-ol (100 mg,0.72 mmol) was reacted with MeCN (5 mL) containing 5-cyano-2-fluoropyridine (88 mg,0.72 mmol) at 60℃for 5h. The reaction mixture was cooled to rt and diluted with water (5 mL). The crude product was extracted into DCM (3X 20 mL) and dried (MgSO ₄ ) And concentrated. The crude product was purified by flash chromatography (silica gel, 0-20% MeOH/EtOAc) to give the product as an orange glass (68 mg, 39% yield).

[M+H] ⁺ ＝241.1

¹ H NMR(CDCl ₃ ,400MHz)δ2.31(1H,dddd,J＝14.0,8.5,5.8,2.5Hz),2.40(1H,ddtd,J＝13.1,6.5,5.2,1.2Hz),3.17-3.33(2H,m),4.03-4.20(2H,m),5.74(1H,dtd,J＝7.2,4.8,2.5Hz),6.79(1H,dd,J＝8.7,0.8Hz),6.86(1H,d,J＝1.3Hz),7.03(1H,d,J＝1.3Hz),7.80(1H,dd,J＝8.7,2.3Hz),8.48(1H,dd,J＝2.4,0.8Hz)

[6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) -3-pyridinyl ] methylamine

Nitrile 6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) pyridine-3-carbonitrile (68 mg,0.28 mmol) was reduced using Raney nickel according to general method 3a over 30 min. The solvent was removed in vacuo to give the product as a pale yellow oil (66 mg, 95% yield).

[M+H] ⁺ ＝245.1

N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) -3-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

Using general procedure 4, [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-yloxy) -3-pyridinyl]Methylamine (66 mg,0.27 mmol) and 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (101 mg,0.27 mmol) and Cs-containing ₂ CO ₃ (177 mg,0.54 mmol) of 1, 4-dioxane (5 mL) was reacted at 60℃for 24h. Cool the reaction to rt, quench and passAnd (5) filtering. The crude product was purified by flash chromatography (silica gel, 0-30% MeOH/EtOAc) to give the product as a colorless glass (52 mg, 36% yield).

[M+H] ⁺ ＝537.3

Deprotection of N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [6- (5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yloxy) -3-pyridinyl ] methyl ] isoquinoline-1, 5-diamine (52 mg,0.1 mmol) was performed using general method 12. The crude product was purified via automated prep HPLC (mass orientation 2-60% in basic mobile phase for 20 min) and lyophilized to give the product as an off-white solid (15 mg, 41% yield).

[M+H] ⁺ ＝387.2

¹ H NMR(DMSO,400MHz)δ2.18-2.26(2H,m),2.92(1H,dd,J＝16.8,5.1Hz),3.15(1H,dd,J＝16.8,4.6Hz),3.94-4.08(2H,m),4.39(2H,d,J＝5.8Hz),5.47-5.58(1H,m),6.49(2H,s),6.55(1H,d,J＝7.6Hz),6.66(1H,t,J＝6.0Hz),6.74(1H,d,J＝8.5Hz),6.82(1H,d,J＝1.2Hz),7.02(1H,d,J＝1.2Hz),7.12-7.19(2H,m),7.32(1H,d,J＝8.3Hz),7.70(1H,dd,J＝8.5,2.5Hz),7.73(1H,d,J＝6.0Hz),8.21(1H,d,J＝2.4Hz)

Example number 4319

N5- [ [2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine

2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] pyridine-4-carbonitrile

Following general method 1b, (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methanol (310 mg,1.87 mmol) is reacted with 4-cyano-2-fluoropyridine (45 mg,3.73 mmol) at 65 ℃ for 4 days. The reaction mixture was cooled to rt, filtered through filter paper and washed with EtOAc (50 mL). The filtrate was purified by flash chromatography (silica gel, 0-100% EtOAc/petroleum ether followed by 0-30% MeOH/EtOAc) to give the product as a brown solid (285 mg, 55% yield).

[M+H] ⁺ ＝269.1

¹ H NMR(400MHz,CDCl ₃ )δ1.76-1.88(m,1H),2.19(s,3H),2.20-2.26(m,1H),2.38-2.51(m,1H),2.61(dd,J＝16.5,10.7Hz,1H),3.08(ddd,J＝16.5,5.0,1.5Hz,1H),3.88(td,J＝11.7,4.8Hz,1H),4.03(ddd,J＝12.4,5.7,3.1Hz,1H),4.28-4.42(m,2H),6.52(d,J＝1.1Hz,1H),7.01(t,J＝1.1Hz,1H),7.09(dd,J＝5.2,1.3Hz,1H),8.28(dd,J＝5.2,0.8Hz,1H)

[2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methylamine

Nitrile 2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] pyridine-4-carbonitrile (284 mg,1.06 mmol) was reduced over 1h using Raney nickel according to general method 3 a. The solvent was removed in vacuo to give the product as a yellow oil (270 mg, 86% yield).

[M+H] ⁺ ＝273.1

Using general procedure 4, 5-bromo-N- [ (2, 4-dimethoxyphenyl) methyl]Isoquinolin-1-amine (136 mg,0.36 mmol) and [2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridin-7-yl) methoxy]-4-pyridinyl]Methylamine (100 mg,0.34 mmol) and 1, 4-dioxane (5 mL) containing NaOtBu (49 mg,0.51 mmol) were reacted at 50℃for 5h. The reaction mixture is passed throughFiltered, washed with EtOAc (40 mL) and MeOH (10 mL) and concentrated. Purification by flash chromatography (silica gel, 0-30% MeOH/DCM)The crude product was obtained as an orange solid (134 mg, 66% yield).

[M+H] ⁺ ＝565.3

Deprotection of N1- [ (2, 4-dimethoxyphenyl) methyl ] -N5- [ [2- [ (2-methyl-5, 6,7, 8-tetrahydroimidazo [1,2-a ] pyridin-7-yl) methoxy ] -4-pyridinyl ] methyl ] isoquinoline-1, 5-diamine (134 mg,0.24 mmol) was performed using general method 12. The crude product was purified by flash chromatography (silica gel, 22% MeOH/DCM) to give the product as an off-white solid (31.0 mg, 38% yield).

[M+H] ⁺ ＝415.2

Example number 9005

N5- ((3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-2-yl) methyl) isoquinoline-1, 5-diamine

3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) 2-cyanopyridine

Following general procedure 4 (using Ruphos Pd G3 as catalyst), 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (227 mg,1.18 mmol) and 5-chloro-3-methyl-2-cyanopyridine (150 mg, 983. Mu. Mol) in a water bath containing CsCO ₃ (961 mg,2.95 mmol) and RuPhos (45.9 mg, 98.3. Mu. Mol) 1, 4-dioxane (3.5 mL) were reacted at 80℃overnight. By flash chromatography (silica gel, 0-5% (containing 0.7M NH) ₃ MeOH/DCM) purification of crudeThe product was obtained as a pale yellow solid (172 mg, 57% yield).

[M+H] ⁺ ＝313.3

¹ H NMR(DMSO,500MHz)δ2.42(s,3H),4.02(t,J＝5.4Hz,2H),4.31(t,J＝5.4Hz,2H),4.95(s,2H),7.53(d,J＝2.9Hz,1H),8.44(d,J＝2.9Hz,1H)

(3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-2-yl) methylamine

Following general method 3a, 3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) 2-cyanopyridine (168 mg,0.55 mmol) was reduced using raney nickel for 6H. The solvent was removed in vacuo to give the product as an off-white solid (105 mg, 57% yield).

[M+H] ⁺ ＝313.3

¹ H NMR(DMSO,500MHz)δ1.88(2H,s),2.26(3H,s),3.71(2H,s),3.80(2H,t,J＝5.5Hz),4.28(2H,t,J＝5.5Hz),4.70(2H,s),7.35(1H,d,J＝2.8Hz),8.21(1H,d,J＝2.8Hz)

N1- (2, 4-Dimethoxybenzyl) -N5- ((3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-2-yl) methyl) isoquinoline-1, 5-diamine

According to general procedure 4, a catalyst containing BrettPhos Pd G4 (14.0 mg,0.05Eq,0.015 mmol) and CsCO was used ₃ (198 mg,0.61 mmol) of 1, 4-dioxane (2 mL) was reacted with (3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-2-yl) methylamine (102 mg, 304. Mu. Mol) and 5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine (113 mg, 304. Mu. Mol) were reacted. The mixture was diluted with EtOAc and concentrated onto silica gel. Flash chromatography (silica gel, 0-5% (0.7M NH) ₃ MeOH)/DCM),the product was obtained as a beige solid (60 mg, 31% yield).

[M+H] ⁺ ＝605.5

¹ H NMR(DMSO,500MHz)δ2.38(3H,s),3.71(3H,s),3.78-3.87(5H,m),4.29(2H,t,J＝5.5Hz),4.41(2H,d,J＝4.6Hz),4.59(2H,d,J＝5.6Hz),4.74(2H,s),6.38(1H,dd,J＝8.4,2.4Hz),6.51-6.61(2H,m),6.79(1H,d,J＝7.8Hz),6.97-7.06(2H,m),7.25(1H,t,J＝8.0Hz),7.37-7.51(3H,m),7.77(1H,d,J＝6.1Hz),8.30(1H,d,J＝2.8Hz)

N1- (2, 4-Dimethoxybenzyl) -N5- ((3-methyl-5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4) using general procedure 12]Triazolo [4,3-a ]]Deprotection of pyrazin-7 (8H) -yl) pyridin-2-yl) methyl isoquinoline-1, 5-diamine (57 mg,0.09 mmol). Flash chromatography (silica gel, 0-10% (0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (33 mg, 80% yield).

[M+H] ⁺ ＝455.4

¹ H NMR(DMSO,500MHz)δ2.37(3H,s),3.84(2H,t,J＝5.5Hz),4.29(2H,t,J＝5.4Hz),4.40(2H,d,J＝4.6Hz),4.74(2H,s),6.45-6.60(3H,m),6.77(1H,d,J＝7.7Hz),7.05(1H,d,J＝6.1Hz),7.21(1H,t,J＝8.0Hz),7.34(1H,d,J＝8.3Hz),7.43(1H,d,J＝2.7Hz),7.76(1H,d,J＝6.1Hz),8.30(1H,d,J＝2.8Hz)

Example number 1282

N5- ((4-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

N5- ((6-chloro-4-methylpyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

A mixture of 6-chloro-4-methylnicotinaldehyde (460 mg,3.01 mmol) and N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (6271 mg,2.01 mmol) in dichloroethane (25 mL) was treated with acetic acid (241 mg,4.01 mmol) and the mixture was stirred at 65℃for 22h followed by at rt for 96h. Additional material from previous reaction was added and the combined mixture was partitioned between DCM (50 mL) and saturated NaHCO ₃ (aqueous solution) (50 mL), and the organic layer was collected. The aqueous layer was washed with additional DCM (50 mL) and the combined organics concentrated in vacuo. The residue was suspended in MeOH (21 mL) and heated to 60 ℃, after which the addition of NaBH was slowed down in portions ₄ (1.49 g,39.4 mmol). After the addition and stirring was completed for 20min, additional NaBH was added in portions ₄ (759 mg,20.1 mmol). THF (10 mL) was added and additional NaBH was used in portions ₄ (759 mg,20.1 mmol) the mixture was treated. After 15min, the solvent was removed in vacuo and the residue partitioned between DCM (50 ml) and saturated NaHCO ₃ (aqueous solution) (50 mL). The aqueous layer was washed with additional DCM (50 mL) and the combined organics were washed with brine (50 mL), dried (Na) ₂ SO ₄ ) Filtered and concentrated in vacuo. Flash chromatography (silica gel, 0-3% (0.7M NH) ₃ MeOH)/DCM) followed by further flash chromatography (silica gel, 0-70% EtOAc/isohexane) to give the product as a white foam (980 mg, 51% yield). The combined fractions were combined and re-purified by flash chromatography (silica gel, 0-70% EtOAc/isohexane) to give more product (156 mg, 9% yield).

[M+H] ⁺ ＝449.4/451.4

¹ H NMR(DMSO,500MHz)δ2.40(3H,d,J＝0.7Hz),3.71(3H,s),3.82(3H,s),4.44(2H,d,J＝5.4Hz),4.59(2H,d,J＝5.6Hz),6.39(1H,dd,J＝8.3,2.4Hz),6.52(1H,d,J＝7.8Hz),6.55(1H,d,J＝2.4Hz),6.57(1H,t,J＝5.6Hz),7.02(1H,d,J＝8.4Hz),7.17(1H,d,J＝6.1Hz),7.21(1H,t,J＝8.0Hz),7.39(1H,s),7.42(1H,t,J＝6.0Hz),7.49(1H,d,J＝8.4Hz),7.75(1H,d,J＝6.1Hz),8.14(1H,s)

N1- (2, 4-Dimethoxybenzyl) -N5- ((4-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

Following general procedure 4 (using Ruphos Pd G3 as catalyst), 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (356 mg,1.86 mmol) and N5- ((6-chloro-4-methylpyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (750 mg,1.55 mmol) in the presence of CsCO ₃ (1.52 g,4.66 mmol) and RuPhos (72.5 mg,0.1Eq, 155. Mu. Mol) in the presence of 1, 4-dioxane (12 mL) at 80℃for 20h. By flash chromatography (silica gel, 0-4% (containing 0.7 NH) ₃ MeOH)/DCM) to give the product as a brown solid (692 mg, 69% yield).

[M+H] ⁺ ＝605.2

¹ H NMR(DMSO,500MHz)δ2.35(3H,s),3.71(3H,s),3.82(3H,s),4.07(2H,t,J＝5.5Hz),4.22(2H,t,J＝5.4Hz),4.33(2H,d,J＝5.1Hz),4.59(2H,d,J＝5.6Hz),4.94(2H,s),6.35-6.42(2H,m),6.54(1H,d,J＝2.4Hz),6.58(1H,d,J＝7.8Hz),6.98(1H,s),7.01(1H,d,J＝8.4Hz),7.15(1H,d,J＝6.2Hz),7.21(1H,t,J＝8.0Hz),7.39(1H,t,J＝5.9Hz),7.45(1H,d,J＝8.4Hz),7.72(1H,d,J＝6.1Hz),8.00(1H,s)

Deprotection of N1- (2, 4-dimethoxybenzyl) -N5- ((4-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (689 mg,1.07 mmol) was carried out using general method 12. The crude product was purified by automated prep HPLC (30-60% mass orientation over 16min in basic mobile phase) followed by lyophilization to give the product as a white solid (315 mg, 65% yield).

[M+H] ⁺ ＝455.2

¹ H NMR(DMSO-d6,500MHz)δ2.34(3H,s),4.07(2H,t,J＝5.4Hz),4.22(2H,t,J＝5.4Hz),4.32(2H,d,J＝5.3Hz),4.94(2H,s),6.33(1H,t,J＝5.4Hz),6.49(2H,s),6.56(1H,d,J＝7.7Hz),6.98(1H,s),7.14-7.20(2H,m),7.33(1H,d,J＝8.3Hz),7.72(1H,d,J＝6.1Hz),8.01(1H,s)

Examples nos. 1303, 1304, and 1305

N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

N1- (2, 4-Dimethoxybenzyl) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

Following general procedure 4 (using Ruphos Pd G3 as catalyst), 8-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (109 mg, 527. Mu. Mol) and N5- ((6-chloro-4-methylpyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (212 mg, 439. Mu. Mol) in a formulation containing CsCO ₃ (429 mg,1.32 mmol) and RuPhos (20.5 mg, 43.9. Mu. Mol) in the presence of 1, 4-dioxane (3.4 mL) at 80℃for 18h. By flash chromatography (silica gel, 0-4% (containing 0.7 NH) ₃ MeOH)/DCM) to give the product as a brown solid (201 mg, 69% yield).

[M+H] ⁺ ＝619.2

¹ H NMR(DMSO,500MHz)δ1.51(3H,d,J＝6.8Hz),2.34(3H,s),3.51(1H,ddd,J＝14.9,11.6,3.9Hz),3.71(3H,s),3.82(3H,s),4.08(1H,td,J＝12.0,4.4Hz),4.23(1H,dd,J＝12.0,3.6Hz),4.32(2H,d,J＝5.1Hz),4.59(2H,d,J＝5.6Hz),4.68(1H,dd,J＝14.6,4.3Hz),5.89(1H,q,J＝6.8Hz),6.30-6.41(2H,m),6.54(1H,d,J＝2.4Hz),6.59(1H,d,J＝7.8Hz),6.93(1H,s),7.01(1H,d,J＝8.4Hz),7.16(1H,d,J＝6.1Hz),7.21(1H,t,J＝8.0Hz),7.39(1H,t,J＝5.9Hz),7.45(1H,d,J＝8.4Hz),7.72(1H,d,J＝6.1Hz),7.99(1H,s)

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N1- (2, 4-Dimethoxybenzyl) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4) was carried out using general procedure 12]Triazolo [4,3-a ]]Deprotection of pyrazin-7 (8H) -yl) pyridin-3-yl) methyl isoquinoline-1, 5-diamine. By flash chromatography (silica gel, 0-8% (containing 0.7M NH) ₃ The crude product was purified with MeOH/DCM) to give the racemate as a beige solid (example No. 1303) (135 mg, 93% yield).

¹ H NMR(DMSO,500MHz)δ1.51(3H,d,J＝6.8Hz),2.34(3H,s),3.46-3.56(1H,m),4.06-4.12(1H,m),4.20 -4.26(1H,m),4.31(2H,d,J＝5.1Hz),4.68(1H,dd,J＝14.5,4.3Hz),5.89(1H,q,J＝6.8Hz),6.31(1H,t,J＝5.4Hz),6.48(2H,s),6.57(1H,d,J＝7.7Hz),6.93(1H,s),7.14-7.20(2H,m),7.33(1H,d,J＝8.3Hz),7.71(1H,d,J＝6.1Hz),7.99(1H,s)

(R) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine and (S) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

Enantiomers were separated by chiral SFC on Sepiatec (UV detection by DAD at 220nm, 40 ℃,120 bar). The column was IG 10X 250mm,5 μm, flow rate 20mL/min,40% MeOH,60% CO ₂ Obtaining the first eluting isomer (R) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-3-yl) methyl isoquinoline-1, 5-diamine (example No. 1304, stereochemistry not confirmed) (50.9 mg, 36% yield)

[M+H] ⁺ ＝469.2

And a second eluting isomer (S x) -N5- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (example number 1305, stereochemistry unidentified) (55.1 mg, 39% yield)

[M+H] ⁺ ＝469.2

¹ H NMR(DMSO-d6,500MHz)δ1.51(3H,d,J＝6.8Hz),2.34(3H,s),3.51(1H,ddd,J＝15.0,11.6,3.8Hz),4.08(1H,td,J＝11.9,4.4Hz),4.23(1H,dd,J＝12.4,3.6Hz),4.31(2H,d,J＝5.3Hz),4.68(1H,dd,J＝14.6,4.3Hz),5.89(1H,q,J＝6.8Hz),6.31(1H,t,J＝5.5Hz),6.49(2H,s),6.57(1H,d,J＝7.7Hz),6.93(1H,s),7.13-7.21(2H,m),7.33(1H,d,J＝8.3Hz),7.71(1H,d,J＝6.1Hz),7.99(1H,s)

Examples nos. 1314, 1315 and 1316

2-chloro-N- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine

To (4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-3-yl) methylamine (97.1 mg, 262. Mu. Mol), 4-bromo-2-chloro-1H-pyrrolo [2,3-b]To a mixture of pyridine (77.0 mg, 249. Mu. Mol) and BrettPhos Pd G3 (11.3 mg, 12.5. Mu. Mol) in degassed 1, 4-dioxane (1.3 mL) was added bis (trimethyl)A solution of lithium amino (1M in THF) (599. Mu.L, 599. Mu. Mol). N for mixtures ₂ (g) Purged and heated at 70 ℃ for 1h. Lithium bis (trimethylsilyl) amide (1M in THF) (299. Mu.L, 299. Mu. Mol) was added and the mixture was heated at 70℃for an additional 1h. BrettPhos Pd G3 (11.3 mg, 12.5. Mu. Mol) and 1, 4-dioxane (1.0 mL) were added and the mixture was heated for an additional 1h. After cooling, acOH (0.4 mL) and MeOH (10 mL) were added to form a solution. The crude solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. Flash chromatography (silica gel, 0-9% (0.7M NH) ₃ MeOH)/DCM) to give the racemate as a pale yellow solid (example No. 1314) (43.5 mg, 35%).

1H NMR(DMSO,500MHz)δ1.52(3H,d,J＝6.8Hz),2.30(3H,s),3.52(1H,ddd,J＝15.0,11.6,3.8Hz),4.08(1H,td,J＝12.0,4.4Hz),4.24(1H,dd,J＝12.3,3.6Hz),4.32(2H,d,J＝5.3Hz),4.70(1H,dd,J＝14.5,4.3Hz),5.90(1H,q,J＝6.8Hz),6.19(1H,d,J＝5.7Hz),6.59(1H,s),6.82(1H,t,J＝5.4Hz),6.95(1H,s),7.76(1H,d,J＝5.6Hz),8.02(1H,s),11.97(1H,s)

(R) -2-chloro-N- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine and (S) -2-chloro-N- ((4-methyl-6- (8-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine

Enantiomers were separated by chiral SFC on a Waters prep100 (with PDA and QDA detector, 40 ℃,120 bar). The column is Chiralpak A1, 5. Mu.M, 21mm by 250mm; 45% MeOH (neutral), 55% CO at a flow rate of 65mL/min ₂ The first eluting isomer (11.9 mg, 9.4%) and the second eluting isomer (11.8 mg, 9.2%) identified as example nos. 1315 and 1316 were obtained (stereochemistry not confirmed).

Example No. 1278

N- ((6- (3- (difluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -2-methyl-1H-pyrrolo [2,3-b ] pyridin-4-amine

To (6- (3- (difluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-3-yl) methylamine (88.3 mg, 315. Mu. Mol), 4-chloro-2-methyl-1H-pyrrolo [2,3-b]To a mixture of pyridine (50.0 mg, 300. Mu. Mol) and BrettPhos Pd G3 (13.6 mg, 15.0. Mu. Mol) was added a solution of lithium bis (trimethylsilyl) amide (1M in THF) (720. Mu.L, 720. Mu. Mol). N for mixtures ₂ (g) Purged and heated at 70 ℃ for 2h. After cooling, acOH (0.2 mL) and MeOH (1 mL) were added. Stirred for 5min, followed by dilution with MeOH (15 mL). The solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH. Flash chromatography (silica gel, 0-8% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (23.7 mg, 19% yield).

[M+H] ⁺ ＝411.3

¹ H NMR(500MHz,DMSO-d6)2.30(3H,s),4.05(2H,t,J＝5.5Hz),4.19(2H,t,J＝5.5Hz),4.34(2H,d,J＝6.0Hz),4.90(2H,s),6.07(1H,d,J＝5.6Hz),6.22(1H,s),6.87(1H,t,J＝6.2Hz),7.05(1H,d,J＝8.7Hz),7.35(1H,t,J＝51.9Hz),7.62(1H,dd,J＝8.7,2.4Hz),7.65(1H,d,J＝5.5Hz),8.20(1H,d,J＝2.3Hz),10.97(1H,s)

Examples nos. 10002, 10003 and 10004

5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-yl) isoquinolin-1-amine

7- (5- (pyrrolidin-2-yl) pyridin-2-yl) -3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazines

Following general procedure 4 (using Ruphos Pd G3 as catalyst), tert-butyl 2- (6-chloropyridin-3-yl) pyrrolidine-1-carboxylate (600 mg,2.12 mmol) was reacted with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (408 mg,2.12 mmol) was reacted in the presence of 1, 4-dioxane (10 mL) containing NaOtBu (408 mg,4.24 mmol) at 90℃for 2h. After cooling, acOH (2 mL) and MeOH (10 mL) were added and the crude product was loaded onto MeOH-containing SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH. The product was redissolved in a mixture of DCM (10.5 mL) and TFA (3.5 mL) and stirred at rt for 2h. The crude product was loaded onto SCX containing MeCN and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH. Flash chromatography (silica gel, 0-10% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (513 mg, 69% yield).

[M+H] ⁺ ＝339.4

¹ H NMR(DMSO,500MHz)δ1.37-1.50(1H,m),1.64-1.82(2H,m),1.98-2.09(1H,m),2.63(1H,brs),2.78 -2.87(1H,m),2.93-3.03(1H,m),3.92(1H,t,J＝7.6Hz),4.08(2H,t,J＝5.5Hz),4.24(2H,t,J＝5.4Hz),4.95(2H,s),7.05(1H,d,J＝8.7Hz),7.62(1H,dd,J＝8.7,2.4Hz),8.13(1H,d,J＝2.4Hz)

N- (2, 4-Dimethoxybenzyl) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-yl) isoquinolin-1-amine

7- (5- (pyrrolidin-2-yl) pyridin-2-yl) -3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4 ]Triazolo [4,3-a ]]Pyrazine (326 mg, 965. Mu. Mol), 5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine (300 mg, 804. Mu. Mol), csCO ₃ (550 mg,1.69 mmol), (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenyl phosphate) (163 mg, 281. Mu. Mol) and Pd ₂ (dba) ₃ (95.7 mg, 104. Mu. Mol) was combined in a flask, and the flask was evacuated and purged with N ₂ (g) And (5) purging. Anhydrous 1, 4-dioxane (7.5 mL) was added, and the mixture was evacuated and N-used ₂ (g) And (5) purging. The mixture was heated to 100℃and held for 18h. Further addition of (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenyl phosphate) (93.0 mg, 161. Mu. Mol) and Pd ₂ (dba) ₃ (73.6 mg, 80.4. Mu. Mol) and the mixture was evacuated and N was used ₂ (g) Purged and heated to 100 ℃ for 24 hours. After cooling, the mixture was treated with AcOH (1 mL) and sonicated. MeOH (20 mL) was added and the crude product was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH. Flash chromatography (silica gel, 0-6% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product as a yellow solid (85 mg, 15% yield).

[M+H] ⁺ ＝631.6

¹ H NMR(DMSO,500MHz)δ1.79-1.97(2H,m),2.05-2.14(1H,m),2.33-2.41(1H,m),2.88-2.95(1H,m),3.70(3H,s),3.81(3H,s),3.97-4.08(3H,m),4.18(2H,t,J＝5.4Hz),4.54(1H,dd,J＝15.8,5.6Hz),4.61(1H,dd,J＝15.8,5.6Hz),4.68-4.74(1H,m),4.86(2H,d,J＝3.3Hz),6.38(1H,dd,J＝8.4,2.4Hz),6.54(1H,d,J＝2.4Hz),6.92(1H,d,J＝8.8Hz),7.01(1H,d,J＝8.4Hz),7.12(1H,d,J＝7.8Hz),7.17-7.26(2H,m),7.51(1H,t,J＝5.9Hz),7.62(1H,dd,J＝8.8,2.4Hz),7.74-7.83(2H,m),8.19(1H,d,J＝2.3Hz)

N- (2, 4-Dimethoxybenzyl) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4) according to general procedure 12 ]Triazolo [4,3-a ]]Deprotection of pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-yl) isoquinolin-1-amine (78 mg,90% Wt,1Eq,0.11 mmol). Flash chromatography (silica gel, 0-10% (0.7M NH) ₃ MeOH)/DCM) to give the racemate as a pale yellow solid (example)Number 10002) (50.6 mg,90% yield).

[M+H] ⁺ ＝481.2

¹ H NMR(DMSO,500MHz)δ1.75-1.97(2H,m),2.04-2.14(1H,m),2.32-2.41(1H,m),2.86-2.95(1H,m),3.91 -4.08(3H,m),4.12-4.22(2H,m),4.70(1H,t,J＝7.9Hz),4.80-4.91(2H,m),6.59(2H,s),6.92(1H,d,J＝8.8Hz),7.09(1H,d,J＝7.6Hz),7.15-7.26(2H,m),7.61(1H,d,J＝8.7Hz),7.66(1H,d,J＝8.2Hz),7.78(1H,dd,J＝6.0,1.7Hz),8.18(1H,s)

(S) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) isoquinolin-1-amine and (R) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-amine

Enantiomers were separated by chiral HPLC on a Gilson UV directed prep (UV detection at 222nm, 25 ℃). The column was iC5×250mm,5um, flow rate 20mL/min,25% water (0.1% DEA), 75% MeCN, to give the first eluting isomer (S) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-yl) isoquinolin-1-amine (example No. 10003, stereochemistry unidentified) (18.4 mg, 33%).

[M+H] ⁺ ＝481.2

And a second eluting isomer (R) -5- (2- (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) pyrrolidin-1-yl) isoquinolin-1-amine (example No. 10004, stereochemistry unidentified) (14.5 mg, 27%).

[M+H] ⁺ ＝481.2

Example number 8459

N5- ((4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) thiophen-2-yl) methyl) isoquinoline-1, 5-diamine

N5- ((4-bromothiophen-2-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

A mixture of 4-bromothiophene-2-carbaldehyde (0.19 g,0.97 mmol) and N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (0.30 g,0.97 mmol) in dichloroethane (15 mL) was treated with AcOH (0.12 g,1.9 mmol) and the mixture stirred at 65deg.C for 18h. The mixture was partitioned between DCM (50 mL) and saturated NaHCO ₃ (aqueous solution) (50 mL), and the organic layer was collected. The aqueous layer was washed with additional DCM (50 mL) and the combined organics concentrated in vacuo. The residue was suspended in MeOH (10 mL) and THF (5 mL) heated to 60℃after which the addition of NaBH was slowed down in portions ₄ (0.37 g,9.7 mmol). After 15min, saturated NaHCO was added ₃ (aqueous solution) (20 mL) and DCM (20 mL). The aqueous layer was washed with additional DCM (50 mL) and the combined organics were washed with brine (50 mL), dried (Na) ₂ SO ₄ ) Filtered and concentrated in vacuo. Flash chromatography (silica gel, 0-70% EtOAc/isohexane) afforded the product as a clear brown oil (0.40 g, 72% yield).

[M+H] ⁺

¹ H NMR(DMSO,500MHz)δ3.71(3H,s),3.82(3H,s),4.61(4H,dd,J＝19.1,5.7Hz),6.39(1H,dd,J＝8.4,2.4Hz),6.55(1H,d,J＝2.4Hz),6.62-6.67(1H,m),6.84(1H,t,J＝6.0Hz),7.02(1H,d,J＝8.4Hz),7.07-7.13(2H,m),7.22(1H,t,J＝8.0Hz),7.40-7.47(2H,m),7.49(1H,d,J＝8.4Hz),7.75(1H,d,J＝6.1Hz)

N1- (2, 4-Dimethoxybenzyl) -N5- ((4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) thiophen-2-yl) methyl) isoquinoline-1, 5-diamine

Following general procedure 4 (using Ruphos Pd G3 as catalyst), N5- ((4-bromothiophen-2-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (400 mg,826 μmol) was reacted with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (190 mg, 991. Mu. Mol) in the presence of CsCO ₃ (803 mg,2.48 mmol) and RuPhos (38.5 mg, 82.6. Mu. Mol) in the presence of 1, 4-dioxane (5 mL) at 80℃for 18h. By flash chromatography (silica gel, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a clear brown oil (300 mg, 48% yield).

[M+H] ⁺ ＝596.0

¹ H NMR(CDCl ₃ ,500MHz)δ1.01(1H,dt,J＝13.4,6.6Hz),1.08-1.20(2H,m),3.51(1H,t,J＝5.5Hz),3.78(3H,s),3.83(3H,s),4.14(1H,t,J＝5.5Hz),4.45(1H,s),4.53-4.63(2H,m),4.72(2H,d,J＝5.3Hz),4.83(1H,t,J＝5.5Hz),5.72(1H,d,J＝6.0Hz),6.19(1H,d,J＝1.8Hz),6.42(1H,dt,J＝8.2,1.9Hz),6.48(1H,d,J＝2.4Hz),6.60-6.79(1H,m),6.79-6.88(2H,m),7.01-7.12(1H,m),7.17-7.28(1H,m),7.28(1H,d,J＝8.3Hz),7.99(1H,dd,J＝6.1,3.0Hz)

Deprotection of N1- (2, 4-dimethoxybenzyl) -N5- ((4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) thiophen-2-yl) methyl) isoquinoline-1, 5-diamine (350 mg, 588. Mu. Mol) was carried out using general procedure 12. The crude product was purified via automated prep HPLC (20-100% mass orientation in basic mobile phase over 12.5 min) to afford the product as a pale yellow solid (160 mg, 61% yield).

[M+H] ⁺ ＝445.9

¹ H NMR(DMSO,500MHz)δ3.63(2H,t,J＝5.5Hz),4.24(2H,t,J＝5.5Hz),4.50-4.57(4H,m),6.44(1H,d,J＝1.8Hz),6.50(2H,s),6.62(1H,d,J＝7.7Hz),6.73(1H,t,J＝5.9Hz),7.11-7.16(2H,m),7.16(1H,t,J＝8.0Hz),7.35(1H,d,J＝8.3Hz),7.74(1H,d,J＝6.0Hz)

Example number 1313

2-chloro-N- ((4-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine

To (4-methyl-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-3-yl) methylamine (85.7 mg, 242. Mu. Mol), 4-bromo-2-chloro-1H-pyrrolo [2,3-b]To a mixture of pyridine (71.0 mg, 230. Mu. Mol) and BrettPhos Pd G3 (10.4 mg, 11.5. Mu. Mol) in degassed 1, 4-dioxane (1.2 mL) was added a solution of lithium bis (trimethylsilyl) amide (1M in THF) (552. Mu.L, 552. Mu. Mol). N for mixtures ₂ (g) Purged and heated at 70 ℃ for 1 hour. After cooling, acOH (0.4 mL) and MeOH (10 mL) were added to form a solution. The solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. Flash chromatography (silica gel, 0-8% (containing 0.7 MNH) ₃ MeOH)/DCM) to give the product as an off-white solid (54 mg, 50%).

[M+H] ⁺ ＝463.3

¹ H NMR(DMSO,500MHz)δ2.31(3H,s),4.08(2H,t,J＝5.4Hz),4.23(2H,t,J＝5.4Hz),4.33(2H,d,J＝5.3Hz),4.96(2H,s),6.18(1H,d,J＝5.7Hz),6.58(1H,s),6.84(1H,t,J＝5.4Hz),6.99(1H,s),7.76(1H,d,J＝5.6Hz),8.04(1H,s),11.98(1H,s)

Example number 1311

N5- ((6- (6-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

6-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine

6-methyl-3- (trifluoromethyl) - [1,2,4]]Triazolo [4,3-a ]]A solution of pyrazine (223 mg,1.10 mmol) and Pd/C (117 mg, 110. Mu. Mol) in MeOH (8 mL) was placed in a hydrogenator vessel with N ₂ (g) Followed by H ₂ (g) Purge, followed by H at 2.5 bar at rt ₂ (g) Stirred for 6.5h. The mixture was filtered, combined with the previous batch and concentrated in vacuo to give the product as a pale yellow solid (77% overall yield).

[M+H] ⁺ ＝207.2

¹ H NMR (cdcl 3,500 mhz) δ1.37 (3H, d, j=6.4 Hz), 3.29-3.39 (1H, m), 3.71 (1H, t, j=11.4 Hz), 4.17 (1H, dd, j=12.3, 4.1 Hz), 4.25 (1H, d, j=16.6 Hz), 4.53 (1H, d, j=16.5 Hz) [ no NH protons are observed ]]

N1- (2, 4-Dimethoxybenzyl) -N5- ((6- (6-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

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Following general procedure 4 (using Ruphos Pd G3 as catalyst), 6-methyl-3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (97.0 mg, 470. Mu. Mol) with N5- ((6-chloropyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (200 mg, 428. Mu. Mol) in a formulation containing RuPhos (20.0 mg, 42.8. Mu. Mol) and CsCO ₃ (418 mg,1.28 mmol) in the presence of 1, 4-dioxane (4 mL) at 80℃for 17h. The reaction mixture was cooled to rt, combined with the previous batch and diluted with EtOAc. The obtained solution is subjected toFiltered and concentrated in vacuo. By flash chromatography (silica gel, 24g cartridge, with 0-20% (containing 0) 7M NH MeOH)/DCM) to give the product as a brown oil. This product was dissolved in 10mL MeOH, 0.15mL AcOH was added and the mixture was passed through a SCX cartridge, washed with 10mL MeOH, and with 3M NH containing ₃ Is eluted with MeOH (50 mL). The ammonia eluate was concentrated in vacuo to give the product as a brown solid (64% overall yield).

[M+H] ⁺ ＝605.0

Deprotection of N1- (2, 4-dimethoxybenzyl) -N5- ((6- (6-methyl-3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine (249 mg, 412. Mu. Mol) was carried out according to general method 12. The reaction mixture was concentrated in vacuo, diluted with MeOH (5 mL), and passed through a SCX cartridge, washed with additional MeOH (15 mL). The product was eluted with 3M NH in MeOH (30 mL). Flash chromatography (silica gel, 12g cartridge, eluting with 0-20% (MeOH with 0.7M NH)/DCM) afforded the product as an orange solid (93 mg, 49% yield).

[M+H] ⁺ ＝455.4

¹ H NMR(DMSO,500MHz)δ1.05(3H,d,J＝6.8Hz),4.21(1H,d,J＝12.6Hz),4.29-4.34(1H,m),4.36(2H,d,J＝5.9Hz),4.43(1H,d,J＝17.3Hz),5.20-5.27(2H,m),6.48(2H,s),6.56(1H,d,J＝7.7Hz),6.63(1H,t,J＝6.0Hz),6.97(1H,d,J＝8.7Hz),7.14(1H,t,J＝8.0Hz),7.17(1H,d,J＝6.1Hz),7.31(1H,d,J＝8.3Hz),7.66(1H,dd,J＝8.7,2.4Hz),7.73(1H,d,J＝6.1Hz),8.26(1H,d,J＝2.4Hz)。

Example No. 1251

2-chloro-N- ((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-c ] pyridin-4-amine

To 5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine (93.0 mg, 383. Mu. Mol) and 4-bromo-2-chloro-1H-pyrrolo [2, 3-c)]To a mixture of pyridine (108 mg, 421. Mu. Mol) in THF (2 mL) was added BrettPhos-Pd-G3 (17.4 mg, 19.1. Mu. Mol). By N ₂ (g) The mixture was degassed and then lithium bis (trimethylsilyl) amide (1M in THF) was added dropwise (919 μl,919 μmol). The mixture was heated at 70℃for 3 days. The mixture was concentrated in vacuo. The residue was resuspended in 1, 4-dioxane (2 mL) and subsequently treated with tBuBrettPhos Pd G3 (16.4 mg,19.1 μmol). By N ₂ (g) The mixture was degassed and then lithium bis (trimethylsilyl) amide (1M in THF) was added dropwise (919 μl,919 μmol). In N ₂ (g) The mixture was heated at 80℃for 1.5h. The mixture was cooled to rt and treated with AcOH (0.2 mL). It was loaded onto SCX resin with MeOH followed by 7N NH ₃ MeOH elution. The crude product was purified by automated prep HPLC (mass orientation, 0.3% aqueous ammonia-MeCN, 10-100% MeCN gradient, 18.5 min) to give the product as a light brown solid (14.5 mg, 9.7% yield).

[M+H] ⁺ ＝385.3

¹ H NMR (500 MHz, methanol-d) ₄ )δ1.25-1.39(m,2H),1.56-1.68(m,1H),1.79-1.86(m,2H),1.98-2.06(m,2H),2.28(s,3H),2.85-2.96(m,2H),3.18(d,J＝6.9Hz,2H),4.35(s,2H),6.54(d,J＝8.6Hz,1H),6.61(s,1H),7.29(s,1H),7.51(dd,J＝8.7,2.4Hz,1H),7.95-8.00(m,2H)。

Example number 1202

2-methyl-N- ((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-b ] pyridin-4-amine

In N ₂ (g) Downward 5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine (128 mg, 547. Mu. Mol), 4-chloro-2-methyl-1H-pyrrolo [2,3-b]Pyridine (76.0 mg, 456. Mu. Mol) and BrettPhos PTo a mixture of d G (20.7 mg, 22.8. Mu. Mol) was added a solution of lithium bis (trimethylsilyl) amide (1M in THF) (1.09 mL,1.09 mmol). The mixture was heated at 70 ℃ for 6h, then left at rt for 12h. AcOH (0.2 mL) and MeOH (1 mL) were added, and after 5min the mixture was diluted with MeOH (15 mL). The crude solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. The crude product was purified by automated prep HPLC (15-45% mass orientation over 12.5min in basic mobile phase) to afford the product as a white solid (105 mg, 61%).

[M+H] ⁺ ＝365.3

¹ H NMR(500MHz,DMSO)1.13(2H,qd,J＝12.0,3.9Hz),1.38-1.50(1H,m),1.64(2H,d,J＝10.8Hz),1.76(2H,td,J＝11.6,2.5Hz),2.11(3H,s),2.29(3H,s),2.67-2.75(2H,m),3.07(2H,t,J＝6.3Hz),4.21(2H,d,J＝5.8Hz),6.07(1H,d,J＝5.5Hz),6.20(1H,d,J＝1.2Hz),6.38-6.45(2H,m),6.68(1H,t,J＝6.0Hz),7.33(1H,dd,J＝8.6,2.4Hz),7.65(1H,d,J＝5.4Hz),7.94(1H,d,J＝2.4Hz),10.91(1H,s)

Example number 1219

N2-methyl-N4- ((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) pyridine-2, 4-diamine

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To a mixture of tert-butyl 5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine (86.9 mg, 371. Mu. Mol), (4-chloropyridin-2-yl) (methyl) carbamate (75.0 mg, 309. Mu. Mol) and BrettPhosPd G3 (14.0 mg,0.05eq, 15.5. Mu. Mol) in THF (0.4 mL) was added a solution of lithium bis (trimethylsilyl) amide (1M in THF) (742. Mu.L, 742. Mu. Mol). The mixture was heated at 70℃for 2h. AcOH (0.2 mL) and MeOH (1 mL) were added to form a solution. The solution was stirred for 5min, then diluted with MeOH (15 mL). The crude solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. The residue was redissolved in a mixture of DCM (3 mL) and TFA (1 mL) and the mixture was stirred at rt for 18h. Will be thickThe product was loaded onto MeOH-containing SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. Flash chromatography (silica gel, 0-45% (0.7M NH) ₃ MeOH)/DCM) to give the product as an off-white solid (33 mg, 30%).

[M+H] ⁺ ＝341.3

¹ H NMR(500MHz,DMSO-d6)1.09-1.19(2H,m),1.39-1.50(1H,m),1.64(2H,d,J＝10.9Hz),1.76(2H,td,J＝11.6,2.5Hz),2.11(3H,s),2.65(3H,d,J＝4.9Hz),2.72(2H,d,J＝11.4Hz),3.08(2H,t,J＝6.3Hz),3.99(2H,d,J＝5.7Hz),5.50(1H,d,J＝2.0Hz),5.78(1H,q,J＝4.9Hz),5.85(1H,dd,J＝5.8,2.0Hz),6.36(1H,t,J＝5.7Hz),6.40-6.47(2H,m),7.29(1H,dd,J＝8.6,2.4Hz),7.49(1H,d,J＝5.8Hz),7.90(1H,d,J＝2.4Hz)

Example number 1232

2-methyl-N- ((6- (((1-methylpiperidin-4-yl) methyl) amino) pyridin-3-yl) methyl) -1H-pyrrolo [2,3-c ] pyridin-4-amine

In N ₂ (g) Downward 5- (aminomethyl) -N- ((1-methylpiperidin-4-yl) methyl) pyridin-2-amine (73.3 mg, 313. Mu. Mol), 4-bromo-2-methyl-1H-pyrrolo [2,3-c]To a mixture of pyridine (55.0 mg, 261. Mu. Mol) and BrettPhos Pd G3 (11.8 mg, 13.0. Mu. Mol) was added a solution of lithium bis (trimethylsilyl) amide (1M in THF) (625. Mu.L, 625. Mu. Mol). The mixture was heated at 70℃for 1.5h. AcOH (0.2 mL) and MeOH (1 mL) were added, and after 5min the mixture was diluted with MeOH (15 mL). The crude solution was loaded onto SCX and washed with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated. The crude product was purified by automated prep HPLC (mass orientation 5-35% in alkaline mobile phase for 17.5 min) to afford the product as a pale yellow solid (27.5 mg, 29%).

[M+H] ⁺ ＝365.3

¹ H NMR(500MHz,DMSO-d6)1.13(2H,qd,J＝3.8,12.0Hz),1.38-1.50(1H,m),1.64(2H,d,J＝11.1Hz),1.76(2H,td,J＝2.5,11.7Hz),2.11(3H,s),2.36(3H,s),2.71(2H,d,J＝11.6Hz),3.06(2H,t,J＝6.2Hz),4.20(2H,d,J＝6.0Hz),5.90(1H,t,J＝6.1Hz),6.32(1H,s),6.36-6.43(2H,m),7.30(1H,s),7.36(1H,dd,J＝2.4,8.6Hz),7.94(1H,s),7.96(1H,d,J＝2.3Hz),10.95(1H,s)

Example number 1274

N5- ((6- (3- (difluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

N5- ((6- (3- (difluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

Following general procedure 4, (6- (3- (difluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridin-3-yl) methylamine (945 mg,3.37 mmol) and 5-bromo-N- (2, 4-dimethoxybenzyl) isoquinolin-1-amine (1.20 g,3.21 mmol) in a solution containing CsCO ₃ (2.09G, 6.42 mmol) and BrettPhos Pd G4 (148 mg, 161. Mu. Mol) in the presence of 1, 4-dioxane (13 mL). The mixture was diluted with EtOAc and concentrated onto silica gel. Flash chromatography (silica gel, 0-6% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow foam (1.56 g, 68%).

[M+H] ⁺ ＝573.4

¹ H NMR(500MHz,DMSO-d6)3.70(3H,s),3.82(3H,s),4.05(2H,t,J＝5.5Hz),4.19(2H,t,J＝5.5Hz),4.36(2H,d,J＝5.8Hz),4.58(2H,d,J＝5.7Hz),4.90(2H,s),6.38(1H,dd,J＝8.4,2.4Hz),6.54(1H,d,J＝2.4Hz),6.57(1H,d,J＝7.8Hz),6.65(1H,t,J＝6.0Hz),7.01(1H,d,J＝8.3Hz),7.04(1H,d,J＝8.7Hz),7.14(1H,d,J＝6.2Hz),7.18(1H,t,J＝8.0Hz),7.23-7.47(3H,m),7.65(1H,dd,J＝8.7,2.4Hz),7.74(1H,d,J＝6.1Hz),8.23(1H,d,J＝2.3Hz)

N5- ((6- (3- (difluoromethyl) -5, 6-dihydro- [1,2, 4) using general procedure 12]Triazolo [4,3-a ]]Deprotection of pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (1.56 g,2.48 mmol). The mixture was diluted with MeCN (100 mL) and loaded onto SCX followed by washing with MeOH. With 0.7M NH ₃ The product was eluted with MeOH and the eluate was concentrated in vacuo. Flash chromatography (silica gel, 0-13% (0.7M NH) ₃ MeOH)/DCM) to give the product, slurried in a minimum amount of MeCN for 1h, followed by filtration. From 9:1MeCN/H ₂ O (10 mL) was freeze-dried to give the product as a white solid (903 mg, 85%).

[M+H] ⁺ ＝423.3

¹ H NMR(500MHz,DMSO-d6)4.05(2H,t,J＝5.4Hz),4.19(2H,t,J＝5.4Hz),4.34(2H,d,J＝5.8Hz),4.90(2H,s),6.48(2H,s),6.54(1H,d,J＝7.7Hz),6.61(1H,t,J＝6.0Hz),7.04(1H,d,J＝8.7Hz),7.13(1H,t,J＝8.0Hz),7.16(1H,d,J＝6.2Hz),7.30(1H,d,J＝8.3Hz),7.35(1H,t,J＝51.9Hz),7.64(1H,dd,J＝8.7,2.4Hz),7.73(1H,d,J＝6.0Hz),8.22(1H,d,J＝2.3Hz)

Example number 1299

N5- ((4-chloro-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) isoquinoline-1, 5-diamine

N5- ((6-bromo-4-chloropyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

A mixture of 6-bromo-4-chloronicotinaldehyde (123 mg, 558. Mu. Mol) and N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (115 mg, 372. Mu. Mol) in dichloroethane (5 mL) was treated with AcOH (44.6 mg, 743. Mu. Mol) and the mixture stirred at 65℃for 20h followed by stirring at rt for 6 days. The mixture was partitioned between DCM (10 mL) and saturated NaHCO ₃ (aqueous solution) (10 mL), and the organic layer was collected. The aqueous layer was washed with additional DCM (5 mL) and the combined organics concentrated in vacuo. The residue was dissolved in a mixture of EtOH (1.2 mL) and THF (2.0 mL) followed by NaBH ₄ (141 mg,3.72 mmol). The mixture was stirred at rt for 2.5h. The solvent was removed in vacuo and the residue partitioned between DCM (10 mL) and water (10 mL). The organic layer was collected with a phase separation cartridge and the aqueous layer was extracted with additional DCM (2×10 mL). The organic phases are combined. Flash chromatography (silica gel, 0-60% EtOAc/isohexane) afforded the product as a white foam (140 mg, 69%).

[M+H] ⁺ ＝513.0/515.0/517.01

¹ H NMR(DMSO,500MHz)δ3.71(3H,s),3.82(3H,s),4.51(2H,d,J＝5.6Hz),4.59(2H,d,J＝5.7Hz),6.39(1H,dd,J＝8.4,2.4Hz),6.48(1H,d,J＝7.7Hz),6.55(1H,d,J＝2.4Hz),6.71(1H,t,J＝5.8Hz),7.02(1H,d,J＝8.4Hz),7.15(1H,d,J＝6.1Hz),7.21(1H,t,J＝8.0Hz),7.45(1H,t,J＝5.8Hz),7.52(1H,d,J＝8.4Hz),7.77(1H,d,J＝6.0Hz),7.95(1H,s),8.26(1H,s)

N5- ((4-chloro-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine

Following general procedure 4 (using Ruphos Pd G3 as catalyst), 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4]Triazolo [4,3-a ]]Pyrazine (10.9 mg, 56.8. Mu. Mol) and N5- ((6-bromo-4-chloropyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (24.3 mg, 47.3. Mu. Mol)) In the presence of RuPhos (2.21 mg, 4.73. Mu. Mol) and CsCO ₃ (46.2 mg, 142. Mu. Mol) in the presence of THF (0.75 mL) was reacted at 80℃for 18h. After cooling, the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with additional EtOAc (10 mL) and the combined organics were washed with brine (10 mL), dried (MgSO) ₄ ) Filtering and concentrating. Flash chromatography (silica gel, 0-3% (0.7M NH) ₃ MeOH)/DCM) to give the product as an orange solid (6.8 mg, 21%).

[M+H] ⁺ ＝625.5/627.4

N5- ((4-chloro-6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4) using general procedure 12]Triazolo [4,3-a ]]Deprotection of pyrazin-7 (8H) -yl) pyridin-3-yl) methyl) -N1- (2, 4-dimethoxybenzyl) isoquinoline-1, 5-diamine (6.2 mg, 8.9. Mu. Mol). The crude product was loaded onto SCX containing MeCN and washed with MeOH. The product was eluted with 0.7M NH in MeOH and the eluate was concentrated. Flash chromatography (silica gel, 0-6% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (3.5 mg, 78% yield).

[M+H] ⁺ ＝475.4/477.4

¹ H NMR(DMSO,500MHz)δ4.10(2H,t,J＝5.5Hz),4.23(2H,t,J＝5.4Hz),4.42(2H,d,J＝5.6Hz),4.99(2H,s),6.54(1H,d,J＝7.8Hz),6.59(1H,t,J＝5.6Hz),6.76(2H,br s),7.16-7.24(2H,m),7.28(1H,s),7.39(1H,d,J＝8.3Hz),7.73(1H,d,J＝6.2Hz),8.10(1H,s)

Example number 2256

N5- (2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) benzyl) isoquinoline-1, 5-diamine

(2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) phenyl) methylamine

2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] using general procedure 3a]Triazolo [4,3-a ]]Reduction of pyrazin-7 (8H) -yl) benzonitrile (278 mg, 893. Mu. Mol). Flash chromatography (silica gel, 12g cartridge, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (247 mg, 84%).

[M+H] ⁺ ＝316.7

¹ H NMR(DMSO,500MHz)δ3.64(2H,s),3.80(2H,t,J＝5.5Hz),4.25(2H,t,J＝5.5Hz),4.68(2H,s),6.88-6.96(2H,m),7.33(1H,t,J＝8.7Hz)

(5- ((2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) benzyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) phenyl) methylamine (136 mg, 430. Mu. Mol) was reacted with methyl (5-bromoisoquinolin-1-yl) carbamate (110 mg, 391. Mu. Mol) and 1, 4-dioxane (2 mL) containing NaOtBu (2M in THF) (391. Mu.L, 783. Mu. Mol) at 75℃for 4H. The reaction mixture was cooled to rt and combined with the previous batch. The resulting mixture was diluted with EtOAc, passed through Filtered and washed with additional EtOAc. Flash chromatography (silica gel, 12g cartridge, 0-20% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a yellow oil (32% overall yield).

[M+H] ⁺ ＝516.3

Treatment with NaOH (aqueous) (2M) (280. Mu.L, 560. Mu. Mol) (5- ((2-fluoro-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]A solution of methyl pyrazin-7 (8H) -yl) benzyl amino) isoquinolin-1-yl carbamate (104.0 mg, 147.3. Mu. Mol) in MeOH (2 mL) was stirred at 65℃for 17H. The mixture was cooled to rt, diluted with EtOAc and washed with brine. The organic layer was dried over MgSO ₄ Drying, filtering and concentrating in vacuum. Flash chromatography (silica gel, 0-20% (0.7M NH) ₃ MeOH)/DCM) and then lyophilized to give the product as a beige solid (57 mg, 81%).

[M+H] ⁺ ＝458.2

¹ H NMR(DMSO,500MHz)δ3.78(2H,t,J＝5.5Hz),4.24(2H,t,J＝5.5Hz),4.39(2H,d,J＝5.8Hz),4.67(2H,s),6.45-6.51(3H,m),6.59(1H,t,J＝6.0Hz),6.86(1H,dd,J＝8.7,2.5Hz),7.00(1H,dd,J＝13.5,2.5Hz),7.14(1H,t,J＝8.0Hz),7.18(1H,d,J＝6.1Hz),7.22(1H,t,J＝8.8Hz),7.31(1H,d,J＝8.4Hz),7.74(1H,d,J＝6.1Hz)

Example number 9002

N5- ((5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrazin-2-yl) methyl) isoquinoline-1, 5-diamine

5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrazine-2-carbonitrile

Treatment of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4 with DIPEA (640. Mu.L, 3.67 mmol) ]Triazolo [4,3-a ]]A solution of pyrazine (361 mg,1.88 mmol) and 5-chloropyrazine-2-carbonitrile (250 mg,1.79 mmol) in anhydrous MeCN (3 mL) was heated in a microwave reactor at 140℃for 6h. The solvent was removed in vacuo. Flash chromatography (silica gel, 0-2.5% (0.7M NH) ₃ MeOH)/DCM) to give the product as a brown solid (460 mg, 87%).

[M-H] ^- ＝294.2

¹ H NMR(DMSO,500MHz)δ4.30(4H,s),5.22(2H,s),8.65(1H,d,J＝1.4Hz),8.69(1H,d,J＝1.4Hz)

(5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrazin-2-yl) methylamine

According to general procedure 3a, 5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrazine-2-carbonitrile (211 mg, 716. Mu. Mol) was reduced over 4H using a Raney nickel cartridge. The solvent was removed in vacuo to give the product as brown glass (203 mg, 90%).

[M-NH] ⁺ ＝283.3

¹ H NMR(DMSO,500MHz)δ2.31(2H,brs),3.73(2H,s),4.14(2H,t,J＝5.5Hz),4.28(2H,t,J＝5.4Hz),5.03(2H,s),8.20(1H,d,J＝1.5Hz),8.47(1H,d,J＝1.5Hz)

(5- (((5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyrazin-2-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyrazin-2-yl) methylamine (100 mg, 334. Mu. Mol) and methyl (5-bromoisoquinolin-1-yl) carbamate (93.9 mg, 334. Mu. Mol) and NaOtBu-containing (64 mg, 668. Mu. Mol)Is reacted at 65℃for 22h with anhydrous THF (2.2 mL). After cooling, the mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2X 10 mL) and the combined organics were washed with brine (10 mL), dried (MgSO) ₄ ) Filtering and concentrating. Flash chromatography (silica gel, 0-9% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (90.5 mg, 43%).

[M+H] ⁺ ＝500.4

¹ H NMR(DMSO,500MHz)δ3.65(3H,s),4.13(2H,t,J＝5.4Hz),4.26(2H,t,J＝5.5Hz),4.51(2H,d,J＝5.9Hz),5.02(2H,s),6.67(1H,d,J＝7.6Hz),7.10(1H,t,J＝6.0Hz),7.24(1H,d,J＝8.4Hz),7.31(1H,t,J＝8.0Hz),7.95(1H,d,J＝6.0Hz),8.20-8.24(2H,m),8.51(1H,d,J＝1.5Hz),9.85(1H,s)

Using general procedure 14a (5- (((5- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4))]Triazolo [4,3-a ]]Deprotection of methyl pyrazin-7 (8H) -yl) pyrazin-2-yl) methyl) amino) isoquinolin-1-yl carbamate (88.0 mg, 138. Mu. Mol). The mixture was partitioned between EtOAc (15 mL) and saturated NH ₄ Cl (aqueous) (15 mL). The aqueous layer was extracted with EtOAc (7 mL) and the combined organics were washed with brine (10 mL), dried (MgSO) ₄ ) Filtering and concentrating. Flash chromatography (silica gel, 0-10% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (24 mg, 39%).

[M+H] ⁺ ＝442.2

¹ H NMR(DMSO,500MHz)δ4.13(2H,t,J＝5.4Hz),4.26(2H,t,J＝5.4Hz),4.46(2H,d,J＝5.7Hz),5.02(2H,s),6.50(2H,s),6.55(1H,d,J＝7.7Hz),6.69(1H,t,J＝6.0Hz),7.10-7.19(2H,m),7.32(1H,d,J＝8.3Hz),7.74(1H,d,J＝6.1Hz),8.17(1H,d,J＝1.4Hz),8.51(1H,d,J＝1.5Hz)

Example number 9004

N5- ((6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridazin-3-yl) methyl) isoquinoline-1, 5-diamine

6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridazine-3-carbonitrile

A solution of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine (361 mg,1.88 mmol) and 6-chloropyridazine-3-carbonitrile (250 mg,1.79 mmol) in anhydrous MeCN (3 mL) was treated with DIPEA (475 mg,3.67 mmol) and the mixture heated in a microwave reactor at 140℃for 3h. The solvent was removed in vacuo. The residue was triturated from the minimum amount of MeCN and filtered to give the product as a pale beige solid (406 mg, 76%).

[M+H] ⁺ ＝296.3

¹ H NMR(DMSO,500MHz)δ4.27-4.37(4H,m),5.23(2H,s),7.62(1H,d,J＝9.7Hz),8.04(1H,d,J＝9.6Hz)

(6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridazin-3-yl) methylamine

According to general procedure 3a, 6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4) was reduced over 24h using a Raney nickel cartridge]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridazine-3-carbonitrile (197mg, 667. Mu. Mol). The solvent was removed in vacuo. Flash chromatography (silica gel, 0-18% (containing 0.7M NH) ₃ MeOH)/DCM) to give the product as a white solid (147 mg, 52%).

[M+H] ⁺ ＝300.3

¹ H NMR(DMSO,500MHz)δ2.30(2H,brs),3.84(2H,s),4.16(2H,t,J＝5.4Hz),4.28(2H,t,J＝5.4Hz),5.07(2H,s),7.53(1H,d,J＝9.4Hz),7.58(1H,d,J＝9.4Hz)

(5- (((6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) pyridazin-3-yl) methyl) amino) isoquinolin-1-yl) carbamic acid methyl ester

Following general procedure 4, (6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4)]Triazolo [4,3-a ]]Pyrazin-7 (8H) -yl) pyridazin-3-yl) methylamine (100 mg, 334. Mu. Mol) was reacted with methyl (5-bromoisoquinolin-1-yl) carbamate (93.9 mg, 334. Mu. Mol) and anhydrous THF (2.2 mL) containing NaOtBu (64 mg, 668. Mu. Mol) at 65℃for 22H. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2X 10 mL) and the combined organics were washed with brine (10 mL), dried (MgSO) ₄ ) Filtering and concentrating. Flash chromatography (silica gel, 0-10% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (63 mg, 33%).

[M+H] ⁺ ＝500.4

¹ H NMR(DMSO,500MHz)δ3.65(3H,s),4.16(2H,t,J＝5.4Hz),4.28(2H,t,J＝5.4Hz),4.63(2H,d,J＝5.9Hz),5.07(2H,s),6.66(1H,d,J＝7.6Hz),7.20(1H,t,J＝6.1Hz),7.25(1H,d,J＝8.4Hz),7.30(1H,t,J＝8.0Hz),7.44 -7.52(2H,m),7.94(1H,d,J＝6.0Hz),8.23(1H,d,J＝6.0Hz),9.86(1H,s)

Using general procedure 14a (5- (((6- (3- (trifluoromethyl) -5, 6-dihydro- [1,2, 4))]Triazolo [4,3-a ]]Deprotection of methyl pyrazin-7 (8H) -yl) pyridazin-3-yl) methyl) amino) isoquinolin-1-yl carbamate (60.0 mg, 106. Mu. Mol). Will be mixedPartition between EtOAc (15 mL) and saturated NH ₄ Cl (aqueous) (15 mL). The aqueous layer was extracted with EtOAc (2X 7 mL) and the combined organics were washed with brine (10 mL), dried (MgSO) ₄ ) Filtering and concentrating. Flash chromatography (silica gel, 0-9% (0.7M NH) ₃ MeOH)/DCM) to give the product as a pale yellow solid (27 mg, 55%).

[M+H] ⁺ ＝442.2

¹ H NMR(DMSO,500MHz)δ4.16(2H,t,J＝5.4Hz),4.28(2H,t,J＝5.4Hz),4.58(2H,d,J＝5.9Hz),5.07(2H,s),6.51(2H,s),6.55(1H,d,J＝7.7Hz),6.82(1H,t,J＝6.1Hz),7.09-7.18(2H,m),7.32(1H,d,J＝8.3Hz),7.42 -7.51(2H,m),7.75(1H,d,J＝6.1Hz)

Examples

Table 11: names of Compounds

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Table 12: examples of the embodiments ¹ H NMR data (solvent d6DMSO unless otherwise indicated)

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Biological methodDetermination of FXIa inhibition

In vitro inhibition of factor XIIa was determined using IC50 assays based on standard literature methods (see, e.g., baeriswyl et al, ACS chem. Biol.,2015,10 (8) 1861; bouckaert et al, european Journal of Medicinal Chemistry 110 (2016) 181). Human factor XIIa (Enzyme Research Laboratories) was incubated with fluorogenic substrate H-DPro-Phe-Arg-AFC (Peptide Protein Science) and various concentrations of test compound at 25 ℃. Protease activity was measured by monitoring the accumulation of fluorescence released from the substrate at 25 ℃ over 5 min. The linear rate of fluorescence increase per minute is expressed as percent (%) activity. The Km of FXIIa cleavage substrate was determined by standard conversion of the Michaelis-Menten equation. Compound inhibitor analysis was performed at substrate Km concentration. IC (integrated circuit) ₅₀ The values were calculated as the Inhibitor Concentration (IC) giving 50% inhibition of the uninhibited enzyme activity (100%) ₅₀ ). The data obtained from this analysis are shown in table 13 below using the following scale:

category(s)	IC ₅₀ (nM)
		A	10-100
B	100-300
		C	300-1,000
D	1,000-3,000
		E	3,000-10,000
F	10,000-40,000
		G	40,000-100,000

For test compounds that did not achieve 50% inhibition, the following scale was used:

category(s)
		H1	>20% inhibition at 40. Mu.M
H2	>20% inhibition at 100. Mu.M
		H3	>20% inhibition at 400. Mu.M

Table 13: human FXIIIa data, molecular weight and LCMS data

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Assay for related protease inhibition

In vitro inhibition of the relevant proteases was determined using IC50 analysis based on standard literature methods (see e.g.Shori et al, biochem. Phacol., 1992,43,1209; bouckaert et al, european Journal o)f Medicinal Chemistry 110 (2016) 181). The enzymatic activities of the human serine proteases plasma kallikrein, KLK1, FXa, plasmin, thrombin and trypsin were analyzed using the appropriate fluorogenic substrate at Km concentration, FXIa at immobilized substrate concentration 100. Mu.M and test compounds at various concentrations. Protease activity was measured by monitoring the accumulation of fluorescence released from the substrate at 25 ℃ over 5 min. The linear rate of fluorescence increase per minute is expressed as percent (%) activity. IC (integrated circuit) ₅₀ The values were calculated as the concentration of inhibitor that gave 50% inhibition of the uninhibited enzyme activity (100%).

The data obtained from this analysis are shown in table 14 using the table shown in table 15.

Table 14: enzyme selectivity data

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Table 15: meter for presenting enzyme selectivity data

Category(s)	IC ₅₀ (nM)
		A	10-100
B	100-300
		C	300-1,000
D	1,000-3,000
		E	3,000-10,000
F	10,000-40,000
		G1	>4,000
G2	>20,000
		G3	>40,000
G4	>100,000

Pharmacokinetics of drugs

Pharmacokinetic studies of the compounds in table 16 were performed to assess the pharmacokinetics of a single intravenous dose and after a single oral dose in male Sprague-Dawley (Sprague-Dawley) rats.

Two rats were given a single intravenous dose of 1mL/kg of a nominal 1mg/mL (1 mg/kg) of a 10% DMSO/10% Cremophor EL/80% SWFI vehicle composition containing the test compound. Example 2191 was administered at 1mL/kg of nominal 2mg/mL (2 mg/kg) using the same vehicle.

Two rats were given a single oral dose of 5mL/kg of a nominal 1mg/mL (5 mg/kg) of a 10% DMSO/10% Cremophor EL/80% SWFI vehicle composition containing test compound. Example 2191 was administered at 5mL/kg of nominal 2mg/mL (10 mg/kg) using the same vehicle.

After intravenous administration, blood samples were collected over a period of 12 hours. Sample times were 2, 5, 15 and 30min followed by 1, 2, 4, 6 and 12h. Following oral administration, blood samples were collected over a 24 hour period. Sample times were 5, 15 and 30min followed by 1, 2, 4, 6, 8, 12 and 24h.

After collection, the blood samples were centrifuged and the plasma fractions were analyzed for test compound concentration by LCMS. Oral bioavailability and half-life calculations were obtained from these studies using Phoenix WinNonlin (v 8.0) and are shown below:

table 16: oral exposure data

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Claims

1. A compound of formula (I),

wherein:

z is 2-pyridone or 4-pyridone,

x is selected from SO ₂ And CR1R2;

R2 is selected from H and small alkyl; or (b)

R1 and R2 are linked together with the carbon atom to which they are attached through an alkylene group to form a 3-, 4-or 5-membered saturated ring;

y is selected from NR12, O and CR3R4;

r3 and R4 are independently selected from H and alkyl; or (b)

b is selected from:

(i) Heteroaryl group ^a ；

(ii) An aryl group;

(iv) Fused 5, 5-bicyclo, 6, 5-bicyclo or 6, 6-bicyclo containing aromatic rings fused to non-aromatic rings, wherein the bicyclo optionally contains one or two N ring membersOptionally substituted with 1, 2 or 3 substituents, up to three substituents independently selected from the group consisting of: alkyl, alkoxy, OH, OCF ₃ Halo, oxo, CN and CF ₃ Wherein the 6, 5-bicyclo ring may be connected via the 6-membered or 5-membered ring;

n is 0, 1 or 2;

AW-is selected from:

-(CHR12)-A、-O-(CHR12)-A、-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -O-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NH-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -NR12-(CH ₂ ) _1-6 -C(＝O)-A、-(CH ₂ ) _0-6 -NH-C(＝O)-(CH ₂ ) _0-6 -A、-C(＝O)NR12-(CH ₂ ) _0-6 -A、-(CH ₂ ) _0-6 -C(＝O)-(C H ₂ ) _0-6 -A、-(CH ₂ ) _0-6 - (phenyl) - (CH) ₂ ) _0-6 -A、-NH-SO ₂ -A and-SO ₂ -NH-A；

A is a 4-to 15-membered monocyclic, bicyclic or tricyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

wherein when a is a tricyclic ring system, each of the three rings in the tricyclic ring system is fused, bridged, or bolted to at least one of the other rings in the tricyclic ring system;

the small alkyl radical being a radical having up to 4 carbon atoms (C ₁ -C ₄ ) Or straight-chain saturated hydrocarbons having 3 to 4 carbon atoms (C ₃ -C ₄ ) Branched saturated hydrocarbons of (2); the small alkyl groups may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: (C1-C6) alkoxy, OH, NR13R14, C (=O) OR13, C (=O) NR13R14, CN, CF ₃ A halo group;

aryl is phenyl, biphenyl or naphthyl; aryl groups may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl, alkoxy, methylenedioxy, ethylenedioxy, OH, halo, CN, - (CH) ₂ ) _0-3 -O-Heteroaryl group ^a Aryl group ^b -O-aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b 、-(CH ₂ ) _0-3 Heteroaryl group ^a 、-C(＝O)OR13、-C(＝O)NR13R14、-(CH ₂ ) _0-3 -NR13R14、OCF ₃ And CF (compact F) ₃ ；

halo is F, cl, br or I;

Heteroaryl group ^b Is a 5-, 6-, 9-, or 10-membered monocyclic ringOr a bicyclic aromatic ring containing 1, 2 or 3 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ ；

r12 is independently selected from H, alkyl or cycloalkyl;

r13 and R14 are independently selected from H, alkyl ^b Aryl group ^b And heteroaryl group ^b Or R13 and R14 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered carbon-containing heterocyclic ring optionally containing a further moiety selected from N, NR, S, SO ₂ And heteroatoms of O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono-or di-substituted with substituents selected from the group consisting of: oxo, alkyl ^b Alkoxy, OH, halo and CF ₃ ；

2. A compound of formula (I) according to claim 1, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein Z is a 6-or 5-membered heteroaromatic ring containing 1 or 2 ring members independently selected from N and S; or phenyl.

3. A compound of formula (I) according to claim 2, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof, wherein Z is selected from pyrazole, phenyl, pyrimidine, pyridine, pyrazine, pyridazine, oxazole, thiophene and thiazole.

4. The compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof,

Wherein the compound is selected from:

5. a compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof, wherein X is CR1R2.

6. A compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof, wherein Y is NR12.

7. A compound of formula (I) according to claim 6, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein Y is NH.

8. A compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof, wherein B is heteroaryl ^a 。

9. A compound of formula (I) according to claim 8, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein Y is at the heteroaryl group ^a At a carbon atom on the ring, to B, and adjacent to the heteroaryl group ^a Both ring atoms of the carbon atom on the ring attached to Y are carbon.

10. A compound of formula (I) according to claim 8, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein B is selected from:

is NH at position 1 ₂ Substituted isoquinolinylOptionally as heteroaryl ^a Further substituted with 1 or 2 substituents;

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionally as heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

11. A compound of formula (I) according to claim 8, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein B is selected from:

6-azaindolylOptionally as heteroaryl ^a Is substituted;

7-azaindolylOptionalEarth, e.g. heteroaryl ^a Is substituted; and

pyridyl groupOptionally as heteroaryl ^a Is substituted.

12. A compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein n is 0 or 1.

13. A compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope and pharmaceutically acceptable salt and/or solvate thereof, wherein AW is selected from-a, -OCH ₂ -A、-CH ₂ O-A、-O-A、-(CH ₂ ) ₂ -A、-NH-CH ₂ -A and-NH- (CH) ₂ ) ₂ -C(＝O)-A。

14. A compound of formula (I) according to any one of the preceding claims, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salts and/or solvates thereof, wherein a is a 4-to 12-membered mono-or bicyclic ring system containing one N ring member and optionally one, two or three other ring members independently selected from N, O and S, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

15. A compound of formula (I) according to claim 14, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein a is a 4-to 12-membered monocyclic or bicyclic ring system containing one N ring member and optionally one or two other ring members independently selected from N and O, optionally wherein said ring system is substituted, where applicable, with 1, 2, 3 or 4 substituents independently selected from: halo, alkyl, OH, oxo, cycloalkyl, alkoxy, - (CH) ₂ ) _0-2 Heteroaryl, heterocycloalkyl ^a 、C(＝O)R12、C(＝O)OR13、C(＝O)NR13R14、NR13R14、CF ₃ 、CN；

16. A compound of formula (I) according to claim 15, or a tautomer, isomer, stereoisomer (including enantiomers, diastereomers and racemic and non-racemic mixtures thereof), deuterated isotope, and pharmaceutically acceptable salt and/or solvate thereof, wherein a is selected from:

17. A compound selected from tables 1a, 1b, 2a, 2b, 3, 4a, 4b, 5a, 5b, 6, 7, 8a, 8b, 8c, 9 and 10, or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof.

18. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable excipient.

19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to claim 18, for use in medicine.

20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutical composition according to claim 18, for use in a method of treatment of a disease or condition associated with factor xlla activity.

21. The compound for use, the pharmaceutically acceptable salt and/or the solvate or the pharmaceutical composition thereof according to claim 20, wherein the disease or condition associated with factor XIIa activity is bradykinin mediated vascular edema, wherein the bradykinin mediated vascular edema is hereditary vascular edema.

22. The compound for use, the pharmaceutically acceptable salt and/or the solvate or the pharmaceutical composition thereof according to claim 20, wherein the disease or condition associated with factor XIIa activity is bradykinin mediated vascular edema, wherein the bradykinin mediated vascular edema is non-hereditary.

23. The compound for use, the pharmaceutically acceptable salt and/or solvate thereof or the pharmaceutical composition for use according to claim 20, wherein the disease or condition associated with factor XIIa activity is a thrombotic disorder.

24. A compound of formula (II),

wherein:

e is selected from CH and N;

g1 is:

g2 is F, cl or Br;

m is 0, 1 or 2;

g3, when present, is independently selected from alkyl, OH, OCF ₃ Aryl group ^b Heteroaryl group ^b Alkoxy, CF ₃ 、CN、-(CH ₂ ) _0-3 -N (G4) (G5), -C (=o) OR12, -C (=o) N R R14 and halo; with the proviso that when m is 1, G3 is not methyl;

g4 and G5 are independently selected from alkyl groups ^b Aryl group ^b And heteroaryl group ^b Or G4 and G5 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-or 7-membered carbon-containing heterocyclic ring, optionally containing a further moiety selected from N, NR, S, SO ₂ And heteroatoms of O, which may be saturated or unsaturated with 1 or 2 double bonds, and which may optionally be mono-or di-substituted with substituents selected from the group consisting of: oxo, alkyl ^b Alkoxy, OH, halo and CF ₃ ；

g8 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

alkyl group ^b Is of up to 10 carbon atoms (C ₁ -C ₁₀ ) Or straight-chain saturated hydrocarbons having 3 to 10 carbon atoms (C ₃ -C ₁₀ ) Branched saturated hydrocarbons of (2); alkyl group ^b Can optionally beSubstituted with 1, 2 or 3 substituents independently selected from the group consisting of: (C) ₁ -C ₆ ) Alkoxy, OH, CN, CF ₃ A halo group;

halo is F, cl, br or I;

Heteroaryl group ^b A 5-, 6-, 9-or 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 ring members independently selected from N, NR, S and O, where applicable; wherein heteroaryl is ^b Can optionally be 12 or 3 substituents independently selected from the group consisting of: alkyl group ^b Alkoxy, OH, halo, CN, aryl ^b 、-(CH ₂ ) _1-3 -aryl group ^b And CF (compact F) ₃ ；

r12 is independently selected from H, alkyl or cycloalkyl;

25. A compound selected from

Or a salt, solvate or solvate of a salt thereof.