HK40046165A

HK40046165A - Pyridinyl and pyrazinyl-(aza)indolsulfonamides

Info

Publication number: HK40046165A
Application number: HK62021035736.9A
Authority: HK
Inventors: C·佩古里耶; L·普罗万; A·卡德纳斯; M·勒德克; C·E·穆勒; J·霍克梅耶; A·埃尔-塔耶博; N·博斯塔; M·拉希德
Original assignee: 优时比制药有限公司
Priority date: 2018-06-19
Filing date: 2019-06-18
Publication date: 2021-10-29

Description

Pyridyl and pyrazinyl- (aza) indole sulfonamides

[ background of the invention ]

G-protein coupled receptors (GPCRs) constitute the largest family of membrane receptors in cells. They transduce extracellular signals to intracellular effector (effector) systems and are involved in a variety of physiological phenomena, thus representing the most common target of pharmaceutical drugs, although current therapies target only a small proportion of GPCRs.

GPCRs respond to a wide range of ligands. As a result of advances in human genome sequencing, it has been identified that about 25% of over 400 GPCRs (excluding olfactory GPCRs) still lack defined physiologically relevant ligands. These receptors are known as "orphan GPCRs". It is expected that the identification of "Desorphonation" and its in vivo effects will elucidate new regulatory mechanisms and thus reveal new drug targets. It remains a matter of debate whether GPR17 is such an orphan receptor. Phylogenetically, GPR17 is closely related to nucleotide P2Y receptor and cysteinylleukotriene (CysLT1, CysLT2) receptor with amino acid sequence identity of about 30% to about 35%, respectively.

Multiple tissue Northern blot (Northern blot) and RT-PCR analysis showed that GPR17 is expressed primarily in the Central Nervous System (CNS) (Ciana et al, 2006, EMBO J25 (19): 4615; Blasius et al, 1998, J Neurochem 70(4):1357) and additionally in the heart and kidney, organs that normally undergo ischemic injury. Two human GPR17 isoforms (isoforms) have been identified that differ only in their N-terminal length. The short GPR17 isoform encodes a 339 amino acid residue protein with a typical rhodopsin-7 transmembrane motif. The prolate forms encode receptors with 28 amino acids more at the N-terminus (Blasius et al, 1998). GPR17 is highly conserved (high conserved) in vertebrate species (90% identity to the amino acid sequence of mouse and rat xenogeneic homologues) which may constitute an advantageous feature for the development of small molecule ligands and animal models in the context of drug discovery.

In the original orphan removal report (void report), the results are based on³⁵SGTP γ S binding and cAMP inhibition assays, as well as single cell calcium imaging, identified GPR17 as a dual receptor for uracil nucleotides and cysteaminyl leukotrienes (cysLTs) LTC4 and LTD4 (Ciana et al, 2006, ibid). Evidence of GPR17 function is provided in different cell (e.g., 1321N1, COS7, CHO, and HEK293 cells) contexts (Ciana et al, 2006, ibid). Next, an independent study confirmed the activation of GPR17 by uracil nucleotides, but failed to generalize activation by CysLT (Benned-Jensen and Rosenkilde,2010, Br J Pharmacol,159(5): 1092). However, a recent independent report (Qi et al,2013, J Pharmacol Ther 347,1, 38; Hennen et al,2013, Sci Signal 6,298) suggested a lack of GPR17 reactivity to both uracil nucleotides and CysLT in different cellular backgrounds stably expressing GPR17 (1321N1, CHO, HEK293 cells). A new modulatory effect of GPR17 has also been proposed: GPR 17-when co-expressed with the CysLT1 receptor-renders the CysLT1 receptor unresponsive to its endogenous lipid mediators LTC4 and LTD 4. Further studies are needed to explore more deeply the pharmacology and function of GPR 17.

Drugs that modulate GPR17 activity may have neuroprotective, anti-inflammatory and anti-ischemic effects and are therefore useful in the treatment of cerebral, cardiac and renal ischemia and stroke (WO 2006/045476), and/or in improving the recovery of these events (Bonfanti et al, Cell Death and Disease,2017,8, e 2871).

GPR17 modulators are also thought to be involved in food intake, insulin and leptin response and are therefore claimed to have a role in the treatment of obesity (WO 2011/113032).

Furthermore, there is strong evidence that GPR17 is involved in the myelination process and that negative GPR17 modulators (antagonists or inverse agonists) may be valuable drugs for treating or alleviating myelination disorders such as multiple sclerosis or spinal cord injury (Chen et al, Nature neuroscience 2009,12(11): 1398-. Recently, two studies showed that adult GPR 17-/-knockout mice (knock-out mice) had faster remyelination (remyelination) than the littermate wild type after LPC-induced demyelination in the spinal cord (Lu et al, Scientific Reports,2018,8:4502) or corpus callosum (Ou et al, j. neurosci, 2016,36(41): 10560). In contrast, activation of GPR17 has been shown to inhibit Oligodendrocyte Precursor Cell (OPC) maturation, thereby preventing efficient myelination (Simon et al, supra). This again confirms the potentially critical role of GPR17 in the remyelination process and as a promising drug target in demyelinating diseases. Thus, the identification of potent and selective GPR17 antagonists or inverse agonists would have significant relevance in the treatment of myelinating diseases.

Several serious myelinating diseases are known to be caused by either a disturbance in myelination, or a loss of myelin, commonly referred to as demyelination, and/or the inability of the body to normally form myelin, sometimes referred to as dysmyelination. Myelinating diseases may be idiopathic diseases or secondary to certain triggering events, such as traumatic brain injury or viral infection. Myelinating diseases may primarily affect the Central Nervous System (CNS), but may also be associated with the peripheral nervous system. Myelinating diseases include, inter alia, multiple sclerosis, neuromyelitis optica (also known as Devic's disease), leukopenia (leucodysdynamics), Guillain-Barr é syndrome and many other diseases, as described in further detail below (see also, for example, Love, J Clin Pathol,59,2006,1151, Fumagalli et al, supra). Neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS) and Multiple System Atrophy (MSA) have also recently been implicated in the reduction of myelination (see, e.g., Ettle et al, Mol Neurobiol 53,2016,3046; Jellinger and Welling, motion Disorders,31,2016; 1767; Kang et al, Nature Neurosci 6,2013,571; Bartzokis, neurohem Res (2007)32: 1655).

Multiple Sclerosis (MS) is a chronic progressive disease. It is an inflammatory autoimmune disease that causes oligodendritic cell damage, demyelination and ultimately loss of axons, resulting in a broad spectrum of signs and symptoms of severe neurological diseases, such as fatigue, dizziness, movement and walking problems, speech and swallowing difficulties, pain and others. MS has several forms, occurring in isolated attacks (relapsing forms) or as new symptoms build up over time (progressive forms). Although some symptoms may disappear completely between independent attacks, serious neurological problems still often exist, especially as the disease progresses to more severe forms. According to the american association of multiple sclerosis statistics, approximately 400,000 people in the united states are diagnosed with MS and up to 250 million people worldwide, with an estimated 10,000 new cases diagnosed in the united states each year. Multiple sclerosis is two to three times more common in women than in men.

There is no known causal treatment or cure for multiple sclerosis or many other myelinating diseases. Treatment is often symptomatic and attempts to improve function and prevent new attacks after an attack by addressing the inflamed part of the disease. Such immunomodulatory drugs are often only moderately effective, particularly if the disease is progressing, but may have side effects and be poorly tolerated. Furthermore, most of the available drugs (e.g. interferon-beta, glatiramer acetate or therapeutic antibodies) are only provided in injectable form and/or are directed against only the inflamed part of the disease and not directly against demyelination other drugs (e.g. corticosteroids) show rather unspecific anti-inflammatory and immunosuppressive effects and may therefore lead to chronic side effects, e.g. manifested as Cushing's syndrome.

Therefore, there is a strong need for a safe and effective drug for the treatment of myelinating diseases (such as MS), preferably for drugs suitable for oral administration. Ideally, such a drug would reverse the demyelination process by reducing demyelination and/or by promoting remyelination of the affected neurons. Compounds effective in reducing GPR17 receptor activity may meet these requirements.

However, only a few compounds are known to be effective in modulating GPR17 activity.

WO 2005/103291 proposes the endogenous molecules 5 aminolevulinic acid (5amino leuvulinic acid, 5-ALA) and Protoplasminogen (PBG) as activating ligands for GPR17, discloses the analgesic effect of GPR17 agonists and proposes the use of GPR17 agonists for the treatment of neuropathic pain and as a tool for GPR17 screening assays. However, the reported affinity of 5-ALA and PBG is very low and the amount required in the assay is significant, i.e. the three-digit micromolar range of 5-ALA or even the mM range of PBG, which makes both compounds unsuitable for use in conventional screening assays or even for therapy. Furthermore, PBG is a chemically unstable reactive compound that rapidly decomposes upon exposure to air and light, and is therefore impractical for routine handling. Thus, these compounds do not provide a promising starting point for the development of therapeutically effective negative GPR17 modulators.

Montelukast (Montelukast) and Prussolast (pranlukast) were originally developed as leukotriene receptor antagonists, and recently they were found to act also on the GPR17 receptor (Ciana et al, EMBO J.2006,25, 4615-phase 4627). However, subsequent functional assays contradicted montelukast (Hennen et al,2013, ibid), whereas pharmacological inhibition of GPR17 with pruilast promoted differentiation of oligodendrocytes in primary mice (Hennen et al,2013, ibid) and rats (Ou et al, j.neurosci.36,2016, 10560-10573). Even the phenotype of pruilast mimics GPR17 inhibition in a lysolecithin model of focal demyelination, as GPR17 knockout and pruilast treated wild-type mice show an earlier onset of remyelination (Ou, ibid). These results strongly support the hypothesis that GPR17 inhibitors offer potential for the treatment of demyelinating diseases in humans.

However, the affinity of montelukast and prukast for GPR17 is only in the high micromolar concentration range ((a))et al, ACS Med. chem. Lett.2014,5, 326-330). Given the high protein binding of both compounds and their poor brain permeability, they are unlikely to reach a sufficiently high free concentration to bind to the GPR17 receptor in an amount suitable for human therapy. Furthermore, it is difficult to interpret the results obtained in vivo for these compounds, since they have a confusing high affinity for the CYSLT1 receptor. Using them to target GPR17, cross-reactivity with other receptors is more complicated.

US 8,623,593 discloses certain indole-2-carboxylic acids as GPR17 agonists and their use in screening assays. However, these derivatives are potent agonists, but are not suitable for down-regulating GPR17 activity in need of treatment of myelinating diseases such as MS. Furthermore, due to their readily ionizable carboxyl groups, such GPR17 agonists do not adequately cross the blood brain barrier and are therefore not suitable lead compounds for the development of negative GPR17 modulators. See also Baqi et al, med. chem. commun.,2014,5,86and et al,2014,ibid。

WO 2013/167177 proposes certain phenyltriazole and benzodiazepine class drug (benzodiazepine) compounds as GPR17 antagonists. However, the disclosed compounds were selected only based on in silico screening results and no biological data was provided at all. The inventors of the present application have so far not been able to demonstrate GPR17 antagonist modulating activity of any so-called ligands proposed by the authors of the previous patent applications.

There is therefore a need to identify potent modulators, preferably negative modulators, in particular inverse agonists of GPR17, which are effective in reducing GPR17 activity, preferably for oral administration.

[ brief description of the drawings ]

FIG. 1 illustrates the effect of Compound I-22 on myelin (myelin) expression in an oligodendritic cell/myelination assay.

[ summary of the invention ]

The present invention relates to compounds which are negative modulators of the GPR17 receptor. In a preferred embodiment, the compounds act as negative agonists at the GPR17 receptor, thereby inhibiting GPR17 which is active in nature (constitutive).

In one embodiment, the compound has the structure of formula I:

wherein X1 is N or C (R7),

r2 is hydrogen or halogen, preferably hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

r6 is selected from halogen, cyano, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl methoxy, phenoxy, benzyloxy, benzyl methoxy, pyridylmethoxy, C_1-3Alkoxy and C_1-3Alkyl, wherein each cycloalkyl, benzyl, pyridyl, alkyl and alkoxy may be selected from halogen, cyano, C_1-2Alkoxy and fluoro C_1-2Substituted by one or more substituents of alkoxy, or

R6 together with R7 and the C atom to which they are attached form a five-or six-membered aromatic or non-aromatic ring, which may comprise one or two ring-forming heteroatoms, wherein the ring is preferably phenyl or pyridyl, and wherein the ring is unsubstituted or substituted by one to three residues R13,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Substituted by alkoxy and cyano radicals, or

As mentioned above, R7 and R6 together form a ring,

r8 is selected from hydrogen, halogen, methoxy, ethoxy, fluoromethoxy and fluoroethoxy,

r10 is selected from hydrogen, cyano, halogen, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl oxy, C_3-5Cycloalkyl methoxy, C_1-4Alkoxy, and C_1-4Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

r13 is independently selected at each occurrence from halogen, hydroxy, cyano, methyl, methoxy, fluoromethyl and fluoromethoxy, and pharmaceutically acceptable salts, solvates, isotopes and co-crystals thereof.

In one embodiment of the compounds of formula I, R6 and R7 together with the carbon atom to which they are attached form unsubstituted or substituted phenyl, unsubstituted or substituted pyridyl, or unsubstituted or substituted C_5-6Cycloalkyl, wherein each substituent of the ring formed by R6 and R7, if present, is preferably selected from fluoro, chloro, cyano, hydroxy, methyl, fluoromethyl, methoxy and fluoromethoxy.

At each occurrence, the compounds of the present invention contain R6 and R7 groups which, together with the ring atoms of the bicyclic ring system to which they are attached, form another ring selected from phenyl and pyridyl, which ring, together with the bicyclic moiety to which it is cyclized, forms a tricyclic moiety, which is preferably selected from 1H-benzo [ g ] indol-3-yl and 1H-pyrrolo [3,2-H ] quinolin-3-yl, respectively. In one embodiment any substitution of the 1H-pyrrolo [3,2-H ] quinolin-3-yl is preferably at position 8, e.g., to give, for example, 8- (fluoromethyl) -1H-pyrrolo [3,2-H ] quinoline.

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is hydrogen or halogen, preferably hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

r6 is selected from halogen, cyano, cyclopropyl, benzyl, benzyloxy, pyridylmethoxy, C_1-2Alkoxy and C_1-2Alkyl, wherein each of cyclopropyl, benzyl, pyridyl, alkyl and alkoxy may be substituted by one or more groups selected from halogen, cyano, C_1-2Alkoxy and fluoro C_1-2Substituent of alkoxy, or

R6 together with R7 and the C atom to which they are attached form a pyridine ring, such that the pyridine group together with its cyclized bicyclic ring system forms a 1H-pyrrolo [3,2-H ] quinoline, wherein the pyridine ring is substituted or preferably unsubstituted by one or two residues R13,

As mentioned above, R7 and R6 together form a ring,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

r13 is independently at each occurrence selected from the group consisting of fluoro, chloro, cyano, hydroxy, methyl, methoxy, fluoromethyl and fluoromethoxy,

and pharmaceutically acceptable salts, solvates, isotopes and co-crystals thereof.

One embodiment relates to compounds of formula I,

wherein

X1 is N or C (R7),

r2 is hydrogen or halogen, preferably hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

r6 is selected from halogen, cyano, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl methoxy, benzyloxy, benzyl methoxy, pyridylmethoxy, C_1-3Alkoxy and C_1-3Alkyl, wherein each cycloalkyl, benzyl, pyridyl, alkyl and alkoxy may be substituted by one or more groups selected from halogen, cyano, C_1-2Alkoxy and fluoro C_1-2The substituent of the alkoxy group is substituted,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Alkoxy and cyano, wherein preferably R7 is selected from hydrogen and halogen, in particular from hydrogen and fluorine,

r10 is selected from hydrogen, halogen, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl oxy, C_3-5Cycloalkyl methoxy, C_1-4Alkoxy, and C_1-4Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is hydrogen or halogen, preferably hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

r6 is selected from halogen, cyano, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl methoxy, benzyloxy, benzyl methoxy, pyridylmethoxy, C_1-3Alkoxy and C_1-3Alkyl, wherein each of cycloalkyl, benzyl, pyridyl, alkyl and alkoxy may be substituted with one or more substituents selected from the group consisting of halogen, cyano, methoxy and fluoromethoxy,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Alkoxy and cyano, and a substituent group of the cyano,

r8 is selected from hydrogen, halogen, methoxy and fluoromethoxy,

r10 is selected from hydrogen, halogen, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl oxy, C_1-4Alkoxy, and C_1-4Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein X1 is N or C (R7),

r2, R4 and R5 are independently selected from hydrogen and fluorine, and are preferably hydrogen,

r6 is selected from halogen, cyano, C_3-5Cycloalkyl, benzyloxy, pyridyl-3-methoxy, pyridin-4-ylmethoxy, C_1-3Alkoxy and C_1-3Alkyl, wherein each of cycloalkyl, benzyl, pyridyl, alkyl and alkoxy may be substituted with one or more substituents selected from the group consisting of halogen, methoxy and fluoromethoxy,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-2Alkoxy, and C_1-2Alkyl, wherein each alkyl and alkoxy may be substituted with one or more substituents selected from the group consisting of halogen, methoxy, fluoromethoxy and cyano,

r8 is selected from hydrogen, halogen and methoxy,

r10 is selected from halogen, C_3-4Cycloalkyl radical, C_3-4Cycloalkyl oxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is a hydrogen atom or a salt thereof,

r4 is hydrogen or fluorine,

r5 is hydrogen or fluorine,

r6 is selected from halogen, cyano, C_3-5Cycloalkyl radical, C_1-3Alkoxy, and C_1-3Alkyl, wherein each cycloalkyl, alkyl and alkoxy may be substituted with one or more substituents selected from the group consisting of halogen, methoxy and fluoromethoxy,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-2Alkoxy, and C_1-2Alkyl, wherein each alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Alkoxy and cyano, and a substituent group of the cyano,

r8 is selected from hydrogen, halogen, methoxy and fluoromethoxy,

r10 is selected from halogen, C_3-4Cycloalkyl radical, C_3-4Cycloalkyl oxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is a hydrogen atom or a salt thereof,

r4 is hydrogen or fluorine, preferably hydrogen,

r5 is hydrogen or fluorine, preferably hydrogen,

r6 is selected from halogen, cyano, cyclopropyl, C_1-2Alkoxy, and C_1-2Alkyl, wherein each alkyl and alkoxy may be substituted with one or more substituents selected from the group consisting of halogen, methoxy and fluoromethoxy,

r8 is selected from hydrogen, halogen, methoxy and fluoromethoxy,

r10 is selected from halogen, C_3-4Cycloalkyl radical, C_3-4Cycloalkyl oxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro C_1-3Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and fluoro,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is a hydrogen atom or a salt thereof,

r4 and R5 are independently selected from hydrogen and fluorine,

r6 is selected from halogen, cyano, cyclopropyl, methoxy, and methyl, wherein each methoxy and methyl may be substituted by one or more substituents selected from halogen, methoxy and fluoromethoxy,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, methoxy and methyl, wherein each methoxy and methyl may be substituted by one or more substituents selected from fluoro, methoxy, fluoromethoxy and cyano,

r8 is selected from hydrogen, halogen, methoxy and fluoromethoxy,

r10 is selected from halogen, C_3-4Cycloalkyl radical, C_3-4Cycloalkyl oxy, C_1-2Alkoxy, and C_1-2Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro C_1-2Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, halogen and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and fluoro,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2 is a hydrogen atom or a salt thereof,

r4 and R5 are independently selected from hydrogen and fluorine,

r6 is selected from halogen, cyano, cyclopropyl, C_1-3Alkoxy and C_1-3Alkyl, wherein each alkoxy and alkyl may be unsubstituted or substituted by one or more halogen, preferably by one or more fluorine atoms,

r7, if present, is selected from hydrogen and halogen, preferably from hydrogen and fluorine,

r8 is selected from hydrogen, halogen, methoxy, fluoromethoxy and fluoroethoxy,

r10 is selected from halogen, ring C_3-5Alkyl radical, C_1-3Alkoxy, and C_1-3Alkyl, wherein each cycloalkyl, alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy and halogenated C_1-2The substituent of the alkoxy group is substituted,

r11 is selected from hydrogen, halogen and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2, R4 and R5 are all hydrogen,

r6 is selected from halogen, cyano, cyclopropyl, methoxy, methyl and isopropyl, wherein each of methoxy and methyl may be unsubstituted or substituted with one or more fluoro,

r7, if present, is selected from hydrogen, fluorine, and chlorine,

r8 is selected from the group consisting of hydrogen, fluoro, methoxy, fluoromethoxy and fluoroethoxy,

r10 is selected from halogen, methyl, cyclopropyl, cyclopropyloxy and C_1-3Alkoxy, wherein each alkoxy may be substituted by one or more groups selected from fluoro, C_1-2Alkoxy and fluoro C_1-2The substituent of the alkoxy group is substituted,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

One embodiment relates to compounds of formula I, wherein

X1 is N or C (R7),

r2, R4 and R5 are all hydrogen,

r6 is selected from halogen, cyano, methyl, fluoromethyl, methoxy and fluoromethoxy,

r7, if present, is selected from hydrogen, fluoro, chloro, cyclopropyloxy and fluoromethyl, and is preferably selected from hydrogen and fluoro,

r8 is selected from hydrogen, fluoro and methoxy,

r10 is selected from halogen, cyclopropyl, and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted with one or more substituents selected from the group consisting of fluoro, methoxy, ethoxy, and fluoro C_1-2The substituent of the alkoxy group is substituted,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

wherein R12, if present, is selected from hydrogen, methoxy and fluoro,

A preferred embodiment relates to compounds of the formula I, in which

R2, R4 and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluoro, chloro, cyclopropyloxy and fluoromethyl,

r8 is selected from hydrogen, fluoro and methoxy,

r10 is selected from halogen and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted by one or more substituents selected from the group consisting of fluoro, cyano and fluoro C_1-2The substituent of the alkoxy group is substituted,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

wherein R12, if present, is selected from hydrogen, methoxy and fluoro,

A preferred embodiment relates to compounds of the formula I, in which

R2, R4 and R5 are all hydrogen,

r6 is selected from fluoro, chloro, cyano, methyl, methoxy, fluoromethoxy and fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen and fluorine,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from the group consisting of chlorine, bromine, cyclopropyl and C_1-2Alkoxy, wherein the alkoxy is substituted with up to three fluorine atoms or a substituent selected from methoxy, fluoromethoxy and fluoroethoxy,

r11 is hydrogen or fluorine,

x2 is N or C (R12),

r12, if present, is hydrogen or fluorine, preferably hydrogen,

A preferred embodiment relates to compounds of the formula I, in which

R2, R4 and R5 are all hydrogen,

r6 is chlorine or difluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluoro, chloro, and fluoromethyl, preferably hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from chlorine, bromine and C_1-2Alkoxy, wherein the alkoxy is substituted by up to three fluorine atoms or by a fluoromethoxy group,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

wherein R12, if present, is hydrogen or fluorine, preferably hydrogen,

A preferred embodiment relates to compounds of formula I wherein R2 is hydrogen.

A preferred embodiment relates to compounds of formula I wherein R4 is hydrogen.

A preferred embodiment relates to compounds of formula I wherein R5 is hydrogen.

A preferred embodiment relates to compounds of formula I wherein R5 is halogen, preferably bromine.

A preferred embodiment relates to compounds of formula I, wherein R2, R4 and R5 are all hydrogen,

a preferred embodiment relates to compounds of formula I wherein R6 is selected from halogen, cyano, fluoromethoxy and fluoromethyl.

A preferred embodiment relates to compounds of formula I wherein R6 is isopropyl.

A preferred embodiment relates to compounds of formula I wherein R6 is selected from chloro or fluoromethyl, preferably from chloro and difluoromethyl.

A preferred embodiment relates to compounds of formula I wherein R6 is fluoromethoxy.

A preferred embodiment relates to compounds of formula I, wherein R6 is methoxy.

A preferred embodiment relates to compounds of formula I wherein R6 is cyano.

A preferred embodiment relates to compounds of formula I wherein R6 and R7 together with the C atom to which they are attached form a phenyl or pyridyl ring, which is unsubstituted or substituted with one or more residues R13, as defined herein.

One preferred embodiment relates to compounds of formula I wherein R6 together with R7 and the C atom to which they are attached form an unsubstituted pyridyl ring; in one embodiment, the pyridyl ring together with the bicyclic ring system to which it is cyclized forms a 1H-pyrrolo [3,2-H ] quinoline group.

A preferred embodiment relates to compounds of formula I wherein R7 is hydrogen.

A preferred embodiment relates to compounds of formula I wherein R7 is selected from fluoro, chloro, cyclopropyloxy, fluoromethyl and fluoromethoxy.

A preferred embodiment relates to compounds of formula I wherein R7 is hydrogen or fluoro.

A preferred embodiment relates to compounds of formula I wherein R8 is selected from hydrogen, fluoro, methoxy and fluoromethoxy, preferably from fluoro and methoxy.

A preferred embodiment relates to compounds of formula I, wherein R8 is methoxy.

A preferred embodiment relates to compounds of formula I wherein R10 is other than hydrogen.

A preferred embodiment relates to compounds of formula I, wherein R10 is selected from halogen, C_3-4Cycloalkyl oxy, C_1-3Alkoxy and C_1-3Alkyl, wherein each alkyl or alkoxy group may be substituted by one or more groups selected from cyano, fluoro, C_1-2Alkoxy, and fluoro C_1-2Substituent of alkoxy.

A preferred embodiment relates to compounds of formula I wherein R10 is selected from halogen, cyclopropyl, and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted by one or more substituents selected from the group consisting of fluoro, methoxy, ethoxy and fluoro C_1-2Substituent of alkoxy.

A preferred embodiment relates to compounds of formula I wherein R10 is selected from halogen, cyclopropyl, methoxy, fluoromethoxy, methoxyethoxy, fluoroethoxy and fluoroethoxymethyloxy.

A preferred embodiment relates to compounds of formula I wherein R10 is selected from halogen, methoxy, ethoxy, fluoromethoxy, fluoroethoxy and fluoromethoxyethoxy.

A preferred embodiment relates to compounds of formula I wherein R10 is selected from chloro, bromo, methoxy, difluoromethoxy, monofluoroethoxy and difluoroethoxy.

A preferred embodiment relates to compounds of formula I wherein R11 is hydrogen or fluoro, preferably fluoro.

A preferred embodiment relates to compounds of formula I wherein R11 is methoxy and R8 is fluoro.

One preferred embodiment relates to compounds of formula I wherein X2 is C (R12) and R12 is hydrogen.

One preferred embodiment relates to compounds of formula I wherein X2 is C (R12) and R12 is hydrogen, R8 is methoxy and R11 is fluoro.

One preferred embodiment relates to compounds of formula I wherein X2 is C (R12) and R12 is fluoro.

A preferred embodiment relates to compounds of formula I, wherein X2 is N, thus having the structure of formula II,

wherein all substituents are as described above for formula I.

In one embodiment, in the compound of formula II,

x1 is N or C (R7),

r2, R4, and R5 are all hydrogen,

r6 is selected from halogen, cyano, methyl, fluoromethyl, methoxy, fluoromethoxy and benzyloxy,

r8 is selected from hydrogen, fluoro and methoxy,

r10 is selected from halogen, cyclopropyl, C_1-2Alkyl, and C_1-2Alkoxy, wherein the alkyl and alkoxy groups may optionally be substituted by one or more groups selected from fluoro, cyano, methoxy and fluoro C_1-2The substituent of the alkoxy group is substituted,

r11 is selected from hydrogen, methoxy and fluoro, preferably from hydrogen and fluoro,

In one embodiment, in the compound of formula II,

x1 is N or C (R7),

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r8 is selected from hydrogen, fluoro, and methoxy,

r10 is selected from halogen, C_1-2Alkyl, and C_1-2Alkoxy, wherein the alkyl and alkoxy groups may optionally be substituted by one or more groups selected from fluoro, cyano and fluoro C_1-2The substituent of the alkoxy group is substituted,

In one embodiment, in the compound of formula II,

x1 is N or C (R7),

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r7, if present, is selected from hydrogen, fluoro, chloro, fluoromethyl and cyclopropyloxy, and is preferably hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from the group consisting of chloro, bromo, methoxy, fluoromethoxy, fluoroethoxy, fluoromethoxyethoxy and fluoroethoxymethyloxy,

r11 is a fluorine atom or a fluorine atom,

A preferred embodiment relates to compounds having the formula II, wherein

R2, R4, and R5 are all hydrogen,

r6 is chlorine or difluoromethyl,

x1 is C (R7),

r7 is selected from hydrogen, fluorine, chlorine and fluoromethyl, and is preferably hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from chlorine, bromine and C_1-2Alkoxy, wherein the alkoxy is substituted by up to three fluorine atoms or by a fluoromethoxy or fluoroethoxy group,

r11 is hydrogen or fluorine,

A particular embodiment relates to compounds of formula I wherein X2 is C (R12), thus having formula III

Wherein all substituents are as described herein for compounds of formula I.

In one embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is selected from halogen, cyano, methyl, methoxy, fluoromethoxy, fluoromethyl and benzyloxy,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, halogen, fluoromethoxy and fluoromethyl, and is preferably hydrogen or fluoro,

r8 is selected from hydrogen, fluorine, C_1-2Alkoxy and fluoro C_1-2An alkoxy group,

r10 is selected from halogen, cyclopropyl, C_1-2Alkyl and C_1-2Alkoxy, wherein the cyclopropyl, alkyl and alkoxy may each optionally be substituted by one or more substituents selected from fluoro, methoxy and fluoro C_1-2The substituent of the alkoxy group is substituted,

r12 is selected from hydrogen, methoxy and fluoro,

In one embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

x1 is N or C (R7),

r7, if present, is hydrogen or fluorine,

r8 is selected from hydrogen, fluoro and methoxy, preferably from fluoro and methoxy,

r10 is selected from halogen, cyclopropyl and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted by one or more groups selected from fluoro, methoxy and fluoro C_1-2The substituent of the alkoxy group is substituted,

r12 is selected from hydrogen and fluorine, and preferably is fluorine,

In one embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluoro, chloro, cyclopropyloxy, fluoromethoxy and fluoromethyl,

r8 is selected from hydrogen, fluoro, and methoxy,

r10 is selected from halogen C_1-2Alkyl and C_1-2Alkoxy, wherein the alkyl and alkoxy groups may optionally be substituted by one or more groups selected from fluoro, cyano and fluoro C_1-2The substituent of the alkoxy group is substituted,

r12 is selected from hydrogen, methoxy and fluoro,

In a preferred embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is selected from chloro, methoxy, fluoromethoxy and fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen and fluorine,

r8 is selected from hydrogen, fluoro and methoxy,

r10 is selected from chloro, bromo, cyclopropyl, methoxy, fluoromethoxy, fluoroethoxy, fluoromethoxyethoxy and fluoroethoxymethyloxy,

r11 is hydrogen or fluorine, preferably fluorine, and

r12 is selected from hydrogen and fluorine, and preferably is hydrogen,

In a preferred embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluoro, chloro, fluoromethoxy and cyclopropyloxy,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine, preferably fluorine, and

r12 is selected from hydrogen, methoxy and fluoro, preferably hydrogen,

In a preferred embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is selected from chloro, cyano, methyl, methoxy, fluoromethoxy and fluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluorine and chlorine,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine, and

r12 is hydrogen or fluorine, preferably hydrogen,

In a preferred embodiment, in the compound of formula III,

r2, R4, and R5 are all hydrogen,

r6 is chlorine or difluoromethyl,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, fluoro, chloro and fluoromethyl, preferably hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from chlorine and C_1-2Alkoxy, wherein the alkoxy is substituted by up to three fluorine atoms or by a fluoromethoxy group,

r11 is hydrogen or fluorine, and

r12 is hydrogen or fluorine, preferably hydrogen,

A particular embodiment relates to compounds of formula I wherein X1 is-C (R7) -and thus has the formula IV,

wherein the other substituents are as described above for formula I.

In one embodiment, in the compound of formula IV,

r2, R4, and R5 are all hydrogen,

r7 is selected from hydrogen, halogen, fluoromethoxy and fluoromethyl, and is preferably hydrogen or fluoro,

x2 is N or C (R12),

r12, if present, is selected from hydrogen, methoxy and fluoro,

In one embodiment, in the compound of formula IV,

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r7 is selected from the group consisting of hydrogen, fluoro, chloro, cyclopropyloxy, cyclopropyl, fluoromethoxy and fluoromethyl,

r8 is selected from hydrogen, fluoro, and methoxy,

x2 is N or C (R12),

r12, if present, is selected from hydrogen, methoxy and fluoro,

A preferred embodiment relates to compounds of formula IV, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chloro, cyano, methoxy, fluoromethoxy, methyl and fluoromethyl,

r7 is selected from hydrogen, halogen, fluoromethyl and fluoromethoxy, and is preferably hydrogen or fluorine,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from halogen, cyclopropyl, methoxy, fluoromethoxy, fluoroethoxy, fluoromethoxyethoxy and fluoroethoxymethyloxy,

r11 is hydrogen or fluorine, and

x2 is N or C (R12),

r12, if present, is hydrogen, methoxy or fluoro, preferably hydrogen,

A preferred embodiment relates to compounds of formula IV, wherein

R2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r7 is selected from the group consisting of hydrogen, fluoro, chloro, fluoromethyl and cyclopropyloxy,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine, and

x2 is N or C (R12),

r12, if present, is hydrogen, methoxy or fluoro, preferably hydrogen,

A preferred embodiment relates to compounds of formula IV, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chloro, methoxy, fluoromethoxy, methyl or fluoromethyl,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from chlorine, bromine and C_1-2Alkoxy, wherein the alkoxy is optionally andpreferably by one to three fluorine atoms or by a fluoromethoxy group,

r11 is hydrogen or fluorine, preferably fluorine,

x2 is N or C (R12), and

wherein R12, if present, is hydrogen or fluorine, preferably hydrogen,

A preferred embodiment relates to compounds of formula IV, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chloro or difluoromethyl,

r7 is selected from hydrogen, fluoro, chloro and fluoromethyl, preferably hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

wherein R12, if present, is hydrogen or fluorine, preferably hydrogen,

One preferred embodiment relates to compounds of formula I, II, III or IV wherein R7 is hydrogen.

A preferred embodiment relates to compounds of formula I wherein X1 is N and thus has the formula V

Wherein all substituents are as described above for formula I.

In one embodiment, in the compound of formula V,

r2, R4, and R5 are all hydrogen,

x2 is N or C (R12),

r12, if present, is selected from hydrogen, methoxy and fluoro,

In one embodiment, in the compound of formula V,

r2, R4, and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r8 is selected from hydrogen, fluoro, and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and fluoro,

A preferred embodiment relates to compounds of formula V, wherein

R2, R4, and R5 are all hydrogen,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine, and

x2 is N or C (R12),

r12, if present, is hydrogen, methoxy or fluoro, preferably hydrogen,

A preferred embodiment relates to compounds of formula V, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chloro or fluoromethyl,

r8 is a methoxy group, and R8 is a methoxy group,

r11 is hydrogen or fluorine, preferably fluorine,

x2 is N or C (R12),

wherein R12, if present, is selected from hydrogen, methoxy and fluoro,

A preferred embodiment relates to compounds of formula V, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chloro, methoxy, fluoromethoxy and fluoromethyl,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from chlorine, bromine and C_1-2Alkoxy, wherein the alkoxy is optionally and preferably substituted with one to three fluorine atoms or with a fluoromethoxy or fluoroethoxy group,

r11 is hydrogen or fluorine, preferably fluorine,

x2 is C (R12) wherein R12 is hydrogen,

A preferred embodiment relates to compounds of formula V, wherein

R2, R4, and R5 are all hydrogen,

r6 is selected from chlorine or difluoromethyl, preferably chlorine,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is hydrogen or fluorine,

x2 is C (R12) wherein R12 is selected from hydrogen, methoxy and fluoro,

In a preferred embodiment of the compounds of formula I, II, III, IV or V,

r2, R4, and R5 are all hydrogen,

r8 is hydrogen or fluorine, preferably fluorine,

r11 is methoxy, X2 is C (R12) and R12 is hydrogen,

and X1, R6 and R10 are as defined in the previous embodiments.

One embodiment relates to compounds of formula I wherein R6 and R7 together with the C atom to which they are attached form a 5 or 6 membered ring, as shown in formula VI:

wherein

n is 0 to 3, preferably 0 or 1,

x3 is a CH or N,

r2 is hydrogen or halogen, preferably hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

r10 is selected from hydrogen, halogen, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl oxy, C_3-5Cycloalkyl methoxy, C_1-4Alkoxy radical, C_1-4Alkyl, each of which is cycloalkyl, cycloalkyloxyAlkyl and alkoxy groups may be substituted by one or more groups selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

r13 is independently at each occurrence selected from the group consisting of halogen, cyano, hydroxy, methyl, methoxy, fluoromethyl and fluoromethoxy,

One embodiment is directed to compounds of formula VI, wherein

n is 0

X3 is N or CH,

r2 is a hydrogen atom or a salt thereof,

r4 is a hydrogen atom or a salt thereof,

r5 is hydrogen or halogen, preferably hydrogen,

r8 is selected from hydrogen, fluoro and methoxy,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

r12, if present, is selected from hydrogen, methoxy and fluoro,

One embodiment is directed to compounds of formula VI, wherein

n is 0,1 or 2, preferably 0 or 1,

x3 is a group represented by the formula N,

r2, R4 and R5 are all hydrogen,

r8 is selected from hydrogen, fluoro and methoxy,

r10 is selected from halogen, cyclopropyl, and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted by one or more groups selected fromFluorine, methoxy, ethoxy, and fluorine C_1-2The substituent of the alkoxy group is substituted,

r11 is hydrogen or fluorine,

x2 is a group represented by the formula N,

r13 is independently at each occurrence selected from the group consisting of halogen, hydroxy, methoxy, fluoromethoxy, methyl and fluoromethyl,

In a particular embodiment of the compound of formula VI, N is 0 and X3 is N.

In a preferred embodiment of the compounds of formula I, II, III, IV, V or VI, R11 is selected from hydrogen and fluoro.

In a preferred embodiment of the compounds of formula I, II, III, IV, V or VI, R11 is fluoro.

In a preferred embodiment of the compounds of formula I, II, III, IV, V or VI, R8 is methoxy, R11 is fluoro, and R12, if present, is hydrogen.

In a particularly preferred embodiment of the compounds of formula I, II, III, IV, V or VI, R2, R4 and R5 are all hydrogen, R8 is methoxy, R11 is fluoro, and R12, if present, is hydrogen, and the other substituents are as described herein.

In a particularly preferred embodiment of the compounds of formula I, II, III, IV or V, R2, R4, R5 and R7, if present, are all hydrogen, R8 is methoxy, R11 is fluoro, and R12, if present, is hydrogen, and the other substituents are as described herein.

In one embodiment of the compounds of formula I, II, III, IV, V or VI, R12 is methoxy, R8 is fluoro, and R11 is selected from hydrogen and fluoro.

In a preferred embodiment of the compounds of formula I, II, III, IV, V or VI, R12 is hydrogen.

One embodiment relates to any of the specific GPR17 modulators described herein, including but not limited to those described in the experimental section herein and in table 7.

One preferred embodiment relates to a compound selected from the group consisting of:

6-chloro-N- [6- (2, 2-difluoroethoxy) -2, 5-difluoropyridin-3-yl ] -1H-indole-3-sulfonamide,

n- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [3,2-H ] quinoline-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [3,2-H ] quinoline-3-sulfonamide,

5-bromo-6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -7-fluoro-1H-indole-3-sulfonamide,

6-cyano-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethoxy) -1H-indole-3-sulfonamide,

n- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-cyclopropyl-5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (5-fluoro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

n- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methoxy-1H-indole-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methoxy-1H-indole-3-sulfonamide,

6-chloro-N- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

n- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methyl-1H-indole-3-sulfonamide,

6-cyano-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

6- (difluoromethyl) -N- (2, 5-difluoro-6-methylpyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6- (difluoromethyl) -N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6- (difluoromethyl) -N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- (6-cyclopropyl-2, 5-difluoropyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

6-chloro-N- (6-cyclopropyl-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

n- [6- (2, 2-difluoroethoxy) -2, 5-difluoropyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide,

6-chloro-N- [6- (difluoromethoxy) -4-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

6-chloro-N- [6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

6-chloro-N- [2- (2, 2-difluoroethoxy) -6-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

n- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (difluoromethoxy) -2-methoxy-3-pyridyl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

n- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

6-chloro-N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

n- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide,

6-chloro-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- (5-chloro-3-methoxypyrazin-2-yl) -1H-indole-3-sulfonamide,

6-chloro-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide,

n- (5-bromo-3-methoxypyrazin-2-yl) -6-chloro-1H-indole-3-sulfonamide,

6-chloro-N- (2, 5-difluoro-6-methylpyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide,

6-chloro-N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (2, 5-difluoro-6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-iodopyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-4-fluoropyridin-3-yl) -1H-indole-3-sulfonamide,

Another preferred embodiment relates to a compound as defined herein having the structure of formula I, II, III, IV, V or VI, or any compound disclosed herein separately, in particular any of compounds I-1-I-72, and preferably the position of the fluorine atom shown in one of the compounds disclosed herein comprises at least one fluorine atom¹⁸A compound of an F isotope. By way of non-limiting example, in the compound 6-chloro-N- (6-chloro-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide, at least one of the two fluorines can be replaced by¹⁸And F is shown by isotope. The same applies to the other fluorine-containing compounds described herein. These contain¹⁸The compounds of F are preferably used as PET tracers (tracers).

Another preferred embodiment relates to a compound having the structure of formula I, II, III, IV, V or VI as defined herein, or any compound disclosed herein separately, in particular any of compounds I-1-I-72, and preferably comprising at least one at the position of the carbon atom indicated herein¹¹A C isotope compound. These contain¹¹The compounds of C are preferably used as PET tracers (tracers).

Another preferred embodiment relates to a compound having the structure of formula I, II, III, IV, V or VI as defined herein, or any compound disclosed herein separately, in particular any of compounds I-1-I-72, and preferably including at least one at the position of the iodine atom shown herein¹²³I、¹²⁵I or¹³¹I isotopic compounds. By way of non-limiting example, in the compound 6-chloro-N- (6-iodopyridin-3-yl) -1H-indole-3-sulfonamide disclosed herein, iodine can be replaced by¹²³I、¹²⁵I or¹³¹I is represented by isotope. Comprises¹²³I、¹²⁵I or¹³¹Compounds of the I isotope are preferably useful as SPECT tracers.

Therapeutic and diagnostic applications

In one aspect, the invention relates to any one of the compounds described herein for use in therapy or diagnosis, in particular for use in the treatment of an animal, in particular in the treatment of a human.

The compounds of the present invention are useful as pharmaceuticals due to their GPR17 modulating properties and for the treatment and/or prevention of various diseases of the CNS system.

An embodiment of the present disclosure is thus the compounds described herein as a medicine, in particular as a medicament for the treatment and/or prevention of a GPR 17-related disease.

A GPR 17-associated disease or disorder is a disease associated with dysfunction of the GPR17 signaling system (e.g., overexpression and/or overactivity of the GPR17 receptor). Without wishing to be bound by any theory, the activity of GPR17 may be increased, prolonged or otherwise altered in certain tissues, for example in Oligodendrocyte Progenitor Cells (OPCs) or during oligodendrocyte maturation, possibly due to the activation of endogenous stimuli, such as inflammatory factors. The high activity of GPR17 prevents oligodendrocyte differentiation and efficient myelination, thus promoting the development or progression of myelination disease (see Chen et al, supra). Thus, negative GPR17 modulators may promote myelination by decreasing or turning off GPR17 activity and by supporting OPC maturation into myelinating oligodendrocytes (see, e.g., Simon et al, supra).

In a preferred aspect, the present invention relates to any one of the compounds described herein for use in therapy or diagnosis for the prevention or treatment of a condition or syndrome selected from and/or associated with a dysmyelination disorder, in particular a demyelinating disorder (e.g. of the central nervous system). In one embodiment, the compounds of the invention are used to promote, stimulate and/or accelerate remyelination in an animal in need thereof. In one embodiment, remyelination associated with administration of a compound of the present invention will prevent or treat a demyelinating disease, such as, but not limited to, multiple sclerosis.

The compounds of the invention are also useful in the treatment or prevention of disorders or syndromes associated with brain tissue damage, cerebrovascular disorders, and certain neurodegenerative diseases.

Recently, neurodegenerative disorders have been closely associated with the loss of myelination. Thus, retained oligodendrocyte glial and myelin function is believed to be a key prerequisite for prevention of axonal and neuronal degeneration (see, e.g., Ettle et al, supra). Thus, negative GPR17 modulators may represent an excellent treatment option for any neurodegenerative disease associated with demyelination and/or affected myelination (e.g., ALS, MSA, alzheimer's disease, huntington's disease, or parkinson's disease).

In a particularly preferred aspect, the compounds of the invention are therefore useful for the prevention and/or treatment of peripheral or central myelinating diseases, in particular myelinating disorders of the central nervous system. In one aspect, the compounds of the invention may be used for the treatment and/or prevention and/or diagnosis of myelinating disorders by oral administration. In a preferred embodiment, the myelinating disorder treated with a compound of the present invention is a demyelinating disorder.

Examples of such myelinating disorders treated and/or prevented by the compounds of the present disclosure are in particular:

multiple Sclerosis (MS), including its various sub-forms,

neuromyelitis optica (also known as Devic's disease)

Chronic recurrent inflammatory optic neuritis, acute disseminated encephalomyelitis,

acute Hemorrhagic Leukoencephalopathy (AHL),

periventricular leukomalacia (perivertericular leukomalacia)

Demyelination caused by viral infection (e.g. via HIV or progressive multifocal leukoencephalopathy),

myelination in the central and extrapontine of the pons (central and extrapontine myelinolysis),

demyelination due to traumatic brain tissue injury, including pressure-induced demyelination, e.g. via tumor

Demyelination for hypoxia, stroke or ischemia or other cardiovascular diseases,

demyelination due to exposure to carbon dioxide, cyanide or other CNS toxins

Hildo comma disease (Schilder's disease),

balo Concentric sclerosis (Balo concentric sclerosis),

-perinatal encephalopathy (perinatal encephalopathgy), and

-neurodegenerative diseases, in particular comprising:

o. Amyotrophic Lateral Sclerosis (ALS)

Alzheimer's Disease (AD)

O multiple System atrophy

Parkinson's disease

Spinocerebellar ataxia (SCA), also known as Spinocerebellar atrophy

Huntington's disease

Psychiatric disorders, such as schizophrenia and bipolar affective disorder (bipolar disorder)

Peripheral myelin diseases, such as leukodystrophy, peripheral demyelinating neuropathy, Dejerine-Sottas syndrome or Charcot-Marie-Tooth disease

Treating or preventing CNS diseases such as demyelinating diseases also includes treating the signs and symptoms associated with such diseases.

For example, the use of the compounds of the invention for the treatment and/or prevention of MS also encompasses the treatment and/or prevention of symptoms and symptoms associated with MS, such as negative effects on the optic nerve (loss of vision, double vision), negative effects on the dorsal spine (loss of sensation), negative effects on the corticospinal tract (spastic weakness), negative effects on the cerebellar pathway (uncoordinated, dysarthria, vertigo, cognitive disorders), negative effects on the medial longitudinal fasciculus (double vision at lateral gaze), negative effects on the spinal trigeminal nerve (facial numbness or pain), negative effects on muscle weakness (impaired swallowing, impaired bladder or intestinal control, spasticity), or psychological effects associated with underlying diseases, such as depression, anxiety or other mood disorders, general weakness, or insomnia.

Accordingly, the compounds of the invention are useful in the treatment of the signs and symptoms of myelinating diseases, particularly demyelinating diseases, such as multiple sclerosis; symptoms and symptoms of MS include, but are not limited to, vision loss, vision disorders, diplopia, sensory loss or impairment, weakness such as spasmodic weakness, motor incoordination, dizziness, cognitive dysfunction, facial numbness, facial pain, swallowing impairment, speech impairment, impaired bladder and/or intestinal control, spasticity, depression, anxiety, mood disorders, insomnia, and fatigue.

In a preferred embodiment, the compounds of the invention are used for the treatment of multiple sclerosis. MS is a heterogeneous myelinating disease and can be manifested in a variety of different forms and stages, including but not limited to relapsing-remitting MS, secondary progressive MS, primary progressive MS, progressive relapsing MS, each depending on activity and disease progression. Thus, in one embodiment, the compounds of the invention are useful in the treatment of various stages and forms of multiple sclerosis.

In one aspect, the compounds of the invention are useful for the treatment and/or prevention of neuromyelitis optica (also known as Devick disease or post Devick syndrome). Neuromyelitis optica is a complex disease characterized by inflammation and demyelination of the optic nerve and spinal cord. Many associated symptoms are similar to MS and include muscle weakness, particularly limb weakness, sensory decline and loss of bladder control.

In one aspect, the compounds of the invention are useful for the prevention and/or treatment of ALS. ALS has recently been associated with oligodendrocyte degeneration and increased demyelination, suggesting that ALS is a target disease for negative GPR17 modulators (Kang et al, supra; Fumagalli et al, Neuropharmacology 104,2016, 82).

In one aspect, the compounds of the invention are useful for the prevention and/or treatment of huntington's disease. Huntington's disease is well described as being associated with affected myelination (Bartzokis et al, supra; Huang et al, Neuron 85,2015,1212).

In one aspect, the compounds of the invention are useful for the prevention and/or treatment of multiple system atrophy. Recently, MSA has been closely associated with demyelination (Ettle supra, Jellinger supra), and strategies for remyelination have been proposed to treat or prevent MSA.

In one aspect, the compounds of the invention are useful for the prevention and/or treatment of alzheimer's disease. It has recently been observed that AD is associated with increased cell death and focal demyelination of oligodendrocytes and represents a pathological process in AD (Mitew et al, Acta neuropathohol 119,2010,567).

One aspect of the present invention pertains to methods of treating any of the diseases or disorders described herein, particularly myelinating diseases, e.g., MS, neuromyelitis optica, ALS, chorea huntington's disease, alzheimer's disease, and the like, by administering to an individual in need thereof, including a human patient, a therapeutically effective amount of a compound of the present invention.

In another aspect, the compounds of the invention are useful for spinal cord injury, perinatal encephalopathy, stroke, ischemia, or cerebrovascular disorders.

In one aspect, the invention relates to a method of preventing and/or treating a condition or syndrome associated with a myelinating condition or a condition or syndrome associated with brain tissue damage, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein. The patient in need of such treatment may be any patient suffering from brain tissue damage (e.g. mechanical, chemical, viral or other trauma).

In one aspect, the invention relates to a method of preventing and/or treating a syndrome or condition associated with a myelinating disorder or a disorder or syndrome associated with stroke or other cerebral ischemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein. A patient in need thereof may be any patient who has recently experienced cerebral ischemia/stroke, which may be caused by occlusion of a cerebral artery, e.g. via embolism or via local thrombosis.

GPR17 has also been recently associated with food intake, insulin control and obesity. According to various reports, negative modulators of GPR17 may be useful in controlling food intake and in the treatment of obesity (see, e.g., Ren et al, Diabetes 64,2015; 3670). Accordingly, one embodiment of the present invention relates to the use of the compounds herein for the prevention and/or treatment of obesity and to methods of treating obesity.

Furthermore, the compounds of the invention may be used for the treatment or prophylaxis of tissues expressing GPR17, such as the heart, lung or kidney. In one embodiment, the compounds of the invention may be used to treat or prevent renal and/or cardiac ischemic conditions.

GPR17 is also associated with pulmonary inflammation and asthma induced, for example, by house dust mites (Maekawa, J Immunol 2010,185(3), 1846-. Thus, the compounds of the present invention are useful in the treatment of asthma or other pulmonary inflammation.

Treatment according to the invention may comprise administration of a compound of the disclosure as a "stand-alone" treatment for CNS diseases, in particular myelinating diseases or disorders, such as MS or ALS. Alternatively, the compounds disclosed herein may be administered in combination therapy with other useful drugs.

In a non-limiting example, a compound according to the invention is combined with another drug with a different mode of action (e.g. an anti-inflammatory or immunosuppressive drug) for the treatment of myelinating diseases (e.g. MS). Such compounds include, but are not limited to: (i) corticosteroids, such as predissone, methylprednisone or dessertone, (ii) interferon beta, such as interferon beta-1a, interferon beta-1 b or pegylated interferon beta-1a, (iii) anti-CD 20 antibodies, such as ocrelizumab, ituximab and ofatumab, (iv) glatiramer salts, such as glatiramer acetate, (v) dimethyl fumarate (dimethylfumarate), (vi) fingolimod (fingolimod) and other sphingosine-1-phosphate receptor modulators, such as perninimod (ponexizate), siponimod (siponimod), ornithimod (hootrimod), or laguinobid (laguinimod) and (dihydrofluorescin-84) dihydrofluorescin inhibitors, such as whey alpha-fluoroquinolone (dihydrofluorescin) or (dihydrofluorescin-4) inhibitors, such as natalizumab, (ix) anti-CD 52 such as alemtuzumab, (x) pamoate quinone (mitoxantrone), (xi) anti-Lingo 1 antibodies, such as opilizumab, or (xii) other immunomodulatory therapies, such as masitinib.

Likewise, if a painful myelinating disorder is to be treated, the compounds of the present invention may be combined with an analgesic. Furthermore, the compounds of the present disclosure may be used in combination with antidepressants to co-treat the psychological effects associated with the underlying myelinating disease being treated.

In combination therapy, two or more active ingredients may be provided via the same formulation or "kit of parts" (i.e. in separate galenic units). Furthermore, the two or more active ingredients, comprising an ingredient of the invention, may be administered to the patient simultaneously or sequentially, e.g. intermittently (intermittent therapy). Additional drugs may be administered by the same mode or different modes of administration. For example, a GPR17 modulator of the present invention may be administered orally, while a second agent may be administered by subcutaneous injection.

In one aspect, the compounds of the invention are useful in the diagnosis and/or monitoring of GPR 17-associated diseases, as further described herein, in particular demyelinating diseases as disclosed herein, preferably in the diagnosis and monitoring of multiple sclerosis.

In one aspect, the compounds of the invention may be used to diagnose and/or monitor the expression, distribution and/or activation of the GPR17 receptor in vivo, for example directly in an individual, for example using molecular imaging techniques, or in vitro, for example by assaying any sample, such as a bodily fluid or tissue taken from an individual. Any such determination of GPR17 activity, expression and/or distribution may be used to predict, diagnose and/or monitor the efficacy and/or suitability and/or appropriate dosage of (a) GPR 17-associated disease, particularly myelinating diseases, including but not limited to, e.g., multiple sclerosis, as described herein, and (b) treatments related to any such GPR 17-associated disease.

In one aspect, the compounds of the invention are useful as PET or SPECT tracers, as further disclosed herein, for in vivo diagnosis and/or disease monitoring. Thereby, the expression, activation and/or distribution of the GPR17 receptor can be measured directly in an individual, for example by imaging a human patient after administration of a GPR17 PET or SPECT tracer of the invention. This may facilitate proper diagnosis of the disease, may help determine applicable treatment options and/or may be useful for monitoring disease progression and/or monitoring or predicting the success of a medical intervention, including the selection of therapeutic drugs and proper administration and/or dosing.

In one embodiment, the PET or SPECT tracer of the invention may be used in combination with a therapeutic drug, i.e., as a companion diagnostic agent, to monitor and/or predict the efficacy and/or safety of the therapeutic drug in a particular individual, or to estimate the appropriate dosage of the drug.

One embodiment relates to the PET or SPECT of the invention in combination with a therapeutic agent as a concomitant Drug (Companion Drug). Therapeutic agents for use with the PET or SPECT tracers of the invention may be selected from (a) unlabeled compounds of the invention, (b) GPR17 modulating compounds that are different from compounds of the invention, and (c) agents for treating myelinating diseases, including but not limited to agents for treating multiple sclerosis that are not GPR17 modulators, as further described herein.

One embodiment relates to a kit comprising:

(a) as a first component, the PET or SPECT tracer of the invention, in particular a PET or PET tracer based on a compound having a structure according to any one of formulae I, II, III, IV, V or VI, as further defined herein, or a structure having any one of the compounds disclosed herein, but having incorporated therein at least one radionuclide suitable for PET or SPECT imaging, preferably selected from the group consisting of¹⁸F、¹¹C、¹²³I、¹²⁵I and¹³¹a radionuclide of I.

(b) As a second component, the therapeutic agent is selected from the following:

i. the compounds of the invention have the structure of any one of formulas I, II, III, IV, V, or VI, as further defined herein, or the structure of any single compound disclosed herein, and do not contain a radionuclide,

a gpr17 modulating compound which is different from the compound of the invention as defined in (i), and

a medicament for the treatment of myelinating diseases, including but not limited to medicaments for the treatment of multiple sclerosis, but which do not have GPR17 modulating activity; such compounds are known to those skilled in the art and include those examples as further described above.

Alternatively, the compounds of the invention may be used in vitro diagnostic tests, e.g. for detecting the appropriate body of an individual-e.g. blood, plasma, urine, saliva or cerebrospinal fluid-for any degree of GPR17 expression, activity and/or distribution.

One embodiment pertains to a method of treating a GPR 17-related disease, particularly a myelinating disease, including but not limited to multiple sclerosis, wherein the method comprises the steps of (a) determining the expression, activity and/or distribution of the GPR17 receptor of an individual, (b) comparing the expression, activity and/or distribution of the GPR17 receptor of the individual to the expression, activity and/or distribution of the GPR17 receptor of one or more healthy individuals or populations, (c) determining the need for medical treatment or prevention of the individual based on a deviation of the expression, activity and/or distribution of GPR17 of the individual from a healthy individual or population, and (d) treating the individual with a deviation of the expression, activity and/or distribution of GPR17 receptor by administering to the individual a therapeutic agent suitable for use in the treatment of a GPR 17-related disease or disorder, particularly by administering a GPR17 modulator, preferably by administration of one or more compounds of the invention. In one embodiment, one of the compounds of the invention is used for determining GPR17 expression, activity and/or distribution, in particular with a PET or SPECT tracer, or by in vitro detection of a body fluid or tissue of the individual using a PET or SPECT tracer of the invention.

In a preferred aspect, the present invention relates to a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier.

For administration as a medicament, the compounds may be used in pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, as further defined herein. The pharmaceutical composition may be suitable for, e.g., oral, intravenous, intramuscular, subcutaneous, nasal, rectal, intracranial, ocular, buccal, or transdermal administration, and may include pharmaceutically acceptable carriers, adjuvants, diluents, stabilizers, and the like.

For example, the compounds of the present invention may be dissolved in oil, propylene glycol or other solvents commonly used to produce injections. Suitable examples of carriers include, but are not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like. The compound of the present invention can be formulated into injections by dissolving, suspending or emulsifying in a water-soluble solvent (e.g., saline and 5% glucose) or a water-insoluble solvent (e.g., vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester and propylene glycol). The formulations (formulations) of the present invention may contain any conventional additives such as solubilizing agents, isotonizing agents, suspending agents, emulsifying agents, stabilizing agents and preservatives.

In one embodiment, the compounds of the invention may be administered orally, for example in the form of tablets, capsules, dragees, powders, granules or in liquid or semi-solid form, including for example syrups, suspensions, emulsions or solutions, as non-limiting examples.

Oral formulations may include, but are not limited to, sustained release agents, disintegrants, fillers, lubricants, stabilizers, antioxidants, flavoring agents, dispersing agents, electrolytes, buffers, dyes, or preservatives. Suitable excipients and formulations are known to those skilled in The art and are disclosed in standard monographs, for example Remington ("The science and practice of pharmacy", Lippincott, Williams & Wilkins,2000) or other sources known to those skilled in The art.

Tablets may be prepared, for example, by mixing at least one compound of the present invention with at least one non-toxic pharmaceutically acceptable excipient (e.g., binder, filler/diluent, disintegrant, plasticizer, etc., and optionally a solvent (aqueous or non-aqueous), and then processing the mixture into tablets by methods including, but not limited to, dry compression, dry granulation, wet granulation, spray drying, or melt extrusion.

Tablets may provide immediate release or sustained release of the compounds of the invention.

Typical sustained release agents are, for example, those which swell on contact with water, such as polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, other cellulose ethers, starch, pregelatinized starch, polymethacrylates, polyvinyl acetate, microcrystalline cellulose, dextrans, and mixtures of these. Non-limiting examples of disintegrants include pregelatinized starch, sodium starch glycolate (sodium starch glycolate), microcrystalline cellulose, sodium carboxymethylcellulose (CMC-Na), cross-linked CMC-Na, and low-substituted hydroxypropyl cellulose, and mixtures thereof. Suitable fillers and binders include, but are not limited to, microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugars, starches (e.g., corn or potato starch), pregelatinized starch, fructose, sucrose, dextrose, dextrans, other sugars such as mannitol, maltitol, sorbitol, lactitol and sucrose, silicified microcrystalline cellulose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium lactate, or mixtures thereof. Lubricants, anti-adherents and/or glidants (glidants) include stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, hydrogenated castor oil, sodium stearyl fumarate, polyethylene glycol (macrogol), glyceryl behenate (glycol dibehenate), talc, corn starch, silicon dioxide, and the like, including mixtures.

The compounds of the invention may also be formulated for parenteral administration by injection, for example by bolus injection (bolus injection) or infusion. Compositions for injection may be provided ready for use, and may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain excipients such as suspending, stabilizing, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water or saline, before use.

For nasal administration or administration by inhalation, the compounds according to the invention may conveniently be delivered in the form of an aerosol spray presentation in the form of a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or gas mixture.

For ocular administration, the compounds used in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH adjusted sterile saline, with or without preservatives (e.g., bactericides or fungicides such as phenylmercuric nitrate, benzalkonium chloride (benzalkonium chloride) or chlorhexidine acetate (chlorohexidine acetate) or, for ocular administration, the compounds may be formulated as ointments such as petrolatum.

For rectal administration, the compounds for use in the present invention may conveniently be formulated as suppositories. These can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the active ingredient. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

In one embodiment, the compounds can be administered transdermally. This mode of administration prevents the first-pass effect of so-called oral administration and moreover allows to provide more constant plasma levels, which is particularly advantageous in some cases. Transdermal forms of the design (e.g. ointments or creams or other transdermal systems such as patches or electrophoretic devices) are generally known in the art, see for example Venkatraman and Gale, Biomaterials 1998, Vol 19, p 1119; praussnitz and Langer, Nat Biotechnology 2008, Vol 26.11 p 1261; WO 2001/47503; WO 2009/000262; WO 99/49852; WO 07/094876.

The preferred dosage level of the compounds according to the invention depends on a variety of factors including the condition and body weight of the patient, the severity of the particular disease, the dosage form, the route and duration of administration, but can be suitably selected by one skilled in the art. In various embodiments, the compound is administered in an amount of 0.001 to 10mg/kg body weight per day, or 0.03 to 1mg/kg body weight per day. Individual doses may range from about 0.1 to 1000mg of active ingredient per day, from about 0.2 to 750mg per day, from about 0.3 to 500mg per day, from 0.5 to 300mg per day, or from 1 to 100mg per day. The dose may be administered once a day, or divided into several doses per day.

Another aspect of the invention is a kit comprising a medicament or pharmaceutical composition as described herein, and instructions for use thereof.

Another aspect of the invention is a package comprising at least one pharmaceutical unit or a pharmaceutical composition comprising at least one compound as described herein, and instructions for use thereof.

Definition of

Any reference to compounds according to the present invention also includes pharmaceutically acceptable salts, solvates, isotopes and co-crystals of such compounds, unless expressly stated otherwise.

The term "pharmaceutically acceptable salt" relates to any salt that a compound may form and is suitable for administration to a subject according to the invention, in particular a human subject. Such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, or with organic acids such as acetic, propionic, hexanoic, cyclopentanepropionic, glycolic, pyruvic, lactic, malonic, succinic, malic, maleic, fumaric, tartaric, citric, benzoic, 3- (4-hydroxybenzoyl) benzoic, cinnamic, mandelic, methanesulfonic, ethanesulfonic, 1, 2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphorsulfonic, 4-methylbicyclo [2.2.2] oct-2-ene-1, 6-carboxylic, glucoheptonic, 3-phenylpropionic, propionic, and the like, Pivalic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid (muconic acid). Other salts include 2, 2-dichloroacetate, adipate, alginate, ascorbate, aspartate, 2-acetamidobenzoate, hexanoate, decanoate, camphorate, cyclohexylamine sulfonate (cyclamate), dodecylsulfate, 1, 2-ethane disulfonate (edisil), ethanesulfonate (esylate), isethionate, formate, hemi-lactobionate, gentisate, glucoheptonate (gluceptate), glucuronate, oxoglutarate, hippurate, lactobionate, 1, 5-naphthalenedisulfonate (napadiilate), xinafoate (xinafoate), nicotinate, oleate, orotate, oxalate, palmitate, pamoate (embonate), pyridonate (pidolate), para-aminosalicylate, sebacate, tannic acid, thiocyanate, undecene (undecylenate), and the like; salts formed when replacing an acidic proton present in a parent compound (parent compound), such as ammonia, arginine, phenethylmethylamine (benethamine), phenethylenediamine (benzathine), calcium, choline, danol (deanol), diethanolamine, diethylamine, ethanolamine, ethylenediamine, methylglucamine (meglumine), glycine, hydrabamine (hydrabamine), imidazole, lysine, magnesium, hydroxyethylmorpholine, piperazine, potassium, epoxy amine, sodium, triethanolamine (tromamine), tromethamine (tromethamine) or zinc.

The present invention includes within its scope solvates of the compounds defined herein. A "solvate" is a crystal formed from the active compound and a second component (solvent), which is a liquid at room temperature in isolated form. Such solvates may be formed with common organic solvents, for example hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcohol solvents such as methanol, ethanol or isopropanol; ether solvents such as diethyl ether or tetrahydrofuran; or an ester solvent such as ethyl acetate. Alternatively, solvates of the compounds herein may be formed with water, in which case they will be hydrates.

The present invention also includes co-crystals within its scope. The term "co-crystal" is used to describe the case where neutral molecular constituents are present in a crystalline compound in a defined stoichiometric ratio. The preparation of drug co-crystals enables modification of the crystalline form of the active pharmaceutical ingredient, which in turn may alter its physicochemical properties without compromising its intended biological activity. Examples of co-crystal formers which may be present in the co-crystal with the active pharmaceutical ingredient include L-ascorbic acid, citric acid, glutaric acid, cinnamic acid, mandelic acid, urea and nicotinamide.

The invention also relates toAll suitable isotopic variations (isotopic variations) of the compounds of the invention are encompassed. An "isotopic variation" or simply "isotope" of a compound of the present invention is defined as an atom, preferably the most abundant isotope, in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³⁵S、¹⁸F and³⁶and (4) Cl. Certain isotopic variations of the present invention, for example, those in which a radioactive isotope such as³H or¹⁴C, useful in drug and/or substrate tissue distribution studies. Tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Isotopes are particularly preferred for their ease of preparation and detectability. Further, with isotopes such as deuterium (i.e. deuterium)²H) Substitution may provide certain therapeutic advantages because metabolic stability is more preferred, e.g., increased in vivo half-life, reduced dosage requirements, and thus may be preferred in some circumstances. Isotopic variations of the compounds of the present invention can generally be prepared by conventional methods using appropriate isotopic variations of appropriate reagents.

Another part of the invention are those compounds in which at least one atom is substituted with a radioisotope (radioisotope) of the same or different atom, useful in vivo imaging techniques such as single-photon emission computed tomography (SPECT) or Positron Emission Tomography (PET).

An example of such isotopic variations of GPR17 modulators useful for SPECT studies (such compounds are referred to herein as "SPECT tracers") is where a GPR17 modulator is introduced^99mTc、¹¹¹In、⁸²Rb、¹³⁷Cs、¹²³I、¹²⁵I、¹³¹I、⁶⁷Ga、¹⁹²Ir or²⁰¹Tl (preferably)¹²³I) The compound of (1). For example,in order to use the compounds of the invention as SPECT tracers, one may use¹²³The I isotope is incorporated into a GPR17 modulator as disclosed herein. As a non-limiting example, to use a compound as a SPECT tracer, one may select from¹²³I、¹²⁵I and¹³¹radionuclides of I are incorporated into the compounds of the invention. In one embodiment, the SPECT tracers of the invention may be based on the structures of halogen-containing GPR17 modulators disclosed herein, wherein the radionuclide¹²³I、¹²⁵I and¹³¹one of I has been introduced into the position of the halogen, preferably an iodine atom.

Accordingly, the term "SPECT tracer of the invention" relates to a compound described in the present patent application and having a structure according to any one of formulae I, II, III, IV, V or VI as further defined herein, or a structure disclosed separately herein, wherein at least one radioisotope suitable for SPECT imaging has been introduced. This includes, but is not limited to^99mTc、¹¹¹In、⁸²Rb、¹³⁷Cs、¹²³I、¹²⁵I、¹³¹I、⁶⁷Ga、¹⁹²IR or²⁰¹Tl。

An example of a GPR17 modulator derivative useful for PET applications (referred to herein as a "PET tracer") is one in which is incorporated¹¹C、¹³N、¹⁵O、¹⁸F、⁷⁶Br or¹²⁴A compound of formula I. For example, to use a compound as a PET tracer, one may use¹⁸The F isotope is incorporated into the compound of the present invention. In one embodiment, the PET tracer may be based on the structure of a fluorine-containing GPR17 modulator disclosed herein, wherein the corresponding radionuclide¹⁸F has been introduced into the position of the fluorine atom. The same applies to the introduction of at least one¹¹C、¹³N、¹⁵O、⁷⁶Br or¹²⁴I instead of introducing "unlabeled" carbon, nitrogen, oxygen, bromine or iodine atoms separately (see, e.g., Pi mlott and Sutherland, Chem Soc Rev 2011,40, 149; van der Born et al, Chem Soc Rev 2017,46, 4709).

Accordingly, the term "PET tracer of the invention" relates toA compound as described in the present patent application and having a structure according to any one of formulae I, II, III, IV, V or VI as further defined herein, or a structure as disclosed herein separately, wherein at least one radioisotope suitable for PET imaging has been incorporated. This includes, but is not limited to¹¹C、¹³N、¹⁵O、¹⁸F、⁷⁶Br or¹²⁴I。

The present invention includes within its scope prodrugs of the compounds of the present invention. Typically, such prodrugs are functional derivatives of the compounds described herein that are readily convertible in vivo, e.g., by endogenous enzymes in the intestine or blood, into the desired GPR17 modulating compound described herein. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of produgs, ed.h. bundgaard, Elsevier, 1985.

Depending on their substitution pattern, the compounds of the present invention may or may not have one or more optical stereocenters, and may or may not be present as different enantiomers or non-enantiomers. Any such enantiomers, diastereomers, or other optical isomers are included within the scope of the present invention.

The compounds of the present invention may also exist in different crystalline forms, i.e. as polymorphs, all of which are included in the present invention.

The compounds of the present invention may be included in a pharmaceutical composition, which may also include a pharmaceutically acceptable carrier. By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or carrier, or other ingredient administered with a compound of the invention, and will be understood by those skilled in the art to be pharmaceutically acceptable.

As described herein, the compounds of the present invention are useful for the prevention and/or treatment of certain diseases or complications in animals, particularly humans.

"preventing" refers to reducing the risk of acquiring a disease or disorder (i.e., causing at least one clinical symptom of the disease not to develop in potentially exposed individuals, particularly human individuals, or predisposed to the disease but not yet experiencing or exhibiting symptoms of the disease).

"treating" any disease or condition includes, in one embodiment, ameliorating the disease or condition (i.e., arresting or reducing the development of the disease or at least reducing one clinical symptom of the disease). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may or may not be discernible by the individual (particularly a human individual), but which is based on or associated with the disease or condition to be treated. In another embodiment, "treating" or "treatment" refers to modulating or alleviating the disease or disorder, either physically (e.g., discernible stability on no discernible symptom), physiologically (e.g., stabilization of a physiological parameter), or both. In another embodiment, "treating" refers to delaying the onset or progression of a disease or disorder. As such, "treatment" includes any causal treatment of the underlying disease or disorder (i.e., a change in the disease), as well as any treatment of the signs and symptoms of the disease or disorder (whether or not there is a change in the disease), and any alleviation or amelioration of the disease or disorder, or signs and symptoms thereof.

"diagnosing" a disease or disorder includes, in one embodiment, identifying and measuring the signs and symptoms associated with the disease. "diagnosing" includes, but is not limited to, detecting and/or measuring decreased, increased or incorrectly (e.g., in time or location) expressed, activated or distributed GPR17 receptor as an indicator (indicator) of a GPR 17-associated disease or disorder as compared to a healthy individual. In one example, GPR17 ligand may be used in the form of a PET or SPECT tracer for such diagnosis, including diagnosis of myelinating disease.

The terms "disease" or "disorder" are used almost interchangeably herein.

"monitoring" refers to observing a disease, condition, or at least one medical parameter over a period of time. "monitoring" also includes observing the effect of a therapeutic drug with the aid of a "concomitant drug".

As used herein, "Companion Diagnostic" refers to a compound that can be used in conjunction with a therapeutic agent in order to determine the suitability of the therapeutic agent for a particular patient (e.g., in terms of safety and efficacy). The use of "Companion diagnostics" may include both Diagnostic and monitoring steps.

The terms "animal" and "individual" encompass humans. The terms "human", "patient" and "human individual" are generally used interchangeably herein, unless specifically indicated otherwise.

The invention also relates to the treatment of a disease or condition in an animal, as described in more detail herein, particularly a human disease or condition, comprising administering a therapeutically effective amount of a compound of the invention. By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject (particularly a human subject), is sufficient to effect such treatment for a disease. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the condition, age, weight, sex, etc., of the individual to be treated, particularly a human individual.

The term "multiple sclerosis" as used herein refers to a disease classified in section G35 of the ICD-10-CM diagnostic code, us version 2018.

The term "GPR 17 modulator" as used herein is intended to describe compounds capable of modulating the activity of the GPR17 receptor, in particular compounds capable of decreasing the activity of GPR 17. Such "negative GPR17 modulators" include GPR17 antagonists capable of blocking the effect of GPR17 agonists, as well as GPR17 inverse agonists also capable of inhibiting the constitutively active GPR17 receptor or receptor variation. Preferred GPR17 modulators of the present invention are inverse GPR17 agonists.

Whenever a number appears in a subscript following "C," the number (whether in parentheses or not) refers to the range of carbon atoms that the group contains directly from the number. For example, "C_1-3"and" (C)_1-3) "both refer to groups as further described herein, which include 1 to 3C atoms.

"alkyl" includes saturated aliphatic hydrocarbon groups. The hydrocarbon chain may be straight or branched. Examples of "alkyl" groups include those having 1-5 carbon atoms ("C_1-5Alkyl "), 1-4 carbon atoms (" C_1-4Alkyl "), 1-3 carbon atoms (" C_1-3Alkyl ") or 1-2 carbon atoms (" C)_1-2Alkyl groups "). This term is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butylIsobutyl, tert-butyl, tert-pentyl and the like. Any number of C atoms in an alkyl or other group may or may not be bracketed herein.

"alkyloxy" and "alkoxy" (together, alk (yl) oxy) as used interchangeably herein comprise the group-OR, wherein R is "alkyl" as further defined and exemplified herein. Particular alk (yl) oxy groups include, for example, methyl (yl) oxy, ethyl (yl) oxy, n-propyl (yl) oxy, isopropyl (yl) oxy, n-butyl (yl) oxy, t-butyl (yl) oxy, sec-butyl (yl) oxy, isobutyl (yl) oxy, and the like.

"halogen" includes fluorine, chlorine, bromine and iodine atoms.

"cyano" means-C.ident.N.

The term "fluoroalkyl" as used herein refers to an "alkyl" group, as described herein, which is substituted with one or more fluorine atoms. Fluoro (C)_1-3) Representative examples of alkyl groups include, but are not limited to, -CF₃、-CHFCHF₂and-CH₂CF₃. A particularly preferred fluoroalkyl group is difluoromethyl-CHF₂。

"fluoroalkoxy" and "fluoroalkoxy" as used interchangeably herein refer to "alk (yl) oxy" groups as described herein, which are substituted with one or more fluorine atoms. Fluorine (C)_1-3) Representative examples of alk (yl) oxy groups include, but are not limited to, -OCF₃、-OCHFCH₂F and-OCH₂CF₃。

The term "fluoromethoxy" as used herein means that the methoxy group is substituted with one to three fluorine atoms. The term "monofluoromethoxy" means that the methoxy group is substituted with one fluorine atom. The term "difluoromethoxy" as used herein means that a methoxy group is substituted with two fluorine atoms. The term "trifluoromethoxy" means that the methoxy group is substituted with three fluorine atoms.

The term "fluoroethoxy" as used herein means that an ethoxy group is substituted with one to three fluorine atoms. The term "monofluoroethoxy" as used herein means that the ethoxy group is substituted with one fluorine atom. Particularly preferred monofluoroethoxy groups are the group-OCH₂CH₂F. The term "difluoroethoxy" as used herein means that the ethoxy group is substituted with two fluorine atoms. A particularly preferred difluoroethoxy group is the group-OCH₂CHF₂. The term "trifluoroethoxy" means that the ethoxy group is substituted with three fluorine atoms. Preferred trifluoroethoxy groups are the group-OCH₂CF₃。

The term "fluoromethoxyethoxy" refers to a terminal fluoromethoxy group, as further defined herein, attached to an ethoxy group. A preferred "fluoromethoxyethoxy" group is difluoromethoxyethoxy, which is prepared from-OCH₂CH₂OCHF₂And (4) showing.

The term "cycloalkyl" as used herein refers to a monovalent group derived from a saturated hydrocarbon, which may be unsubstituted or substituted with one or more substituents as further indicated herein. "cycloalkyl" contains at least three and up to, for example, 5 ring-forming carbon atoms ("C)_3-5Cycloalkyl ") or 4 ring-forming atoms (" C)_3-4Cycloalkyl "). Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, and cyclopentyl.

The term "benzyloxy" or "phenylmethoxy" as used herein refers to a compound wherein the phenyl ring and methoxy are linked to represent the group-O-CH₂-a group of phenyl groups.

The term "benzylmethoxy" as used herein refers to a phenylethoxy group wherein a phenyl ring is attached to an ethoxy group to represent the group-O-CH₂-CH₂-phenyl.

The term "pyridylmethoxy" refers to a pyridyl group and a methoxy group linked to represent the group-O-CH₂-a pyridyl group, wherein pyridyl may be any pyridyl group. Preferred pyridylmethoxy radicals in connection with the present invention are

Pyridin-3-ylmethoxyAnd pyridin-4-ylmethoxy

[ embodiment ] A method for producing a semiconductor device

Experimental part:

A. chemistry

The compounds of the invention and their synthetic routes are described in more detail below.

A-I general Process for the manufacture of the Compounds

The compounds of formula I according to the invention can be prepared by conventional methods analogous to those understood by those skilled in the art of synthetic organic chemistry.

Any reference herein to the synthesis of compounds of formula I is equally applicable to the applicable compounds of formulae II, III, IV and V, as well as the specific example compounds disclosed herein.

According to one embodiment, some compounds of formula I may be prepared by the reaction of a compound of formula XI with an aniline of formula X, according to the following formula:

this reaction can be carried out with chlorosulfonic acid to form the non-isolated sulfonyl chloride intermediate XII in a polar solvent such as acetonitrile at a temperature of 60 to 120 ℃. The intermediate XII is then reacted directly with aniline X in a polar solvent, such as acetonitrile, in the presence of a base, such as pyridine, with or without catalytic amounts of 4-Dimethylaminopyridine (DMAP), at a temperature preferably between 60 and 80 ℃.

Alternatively, sulfonyl chloride intermediate XII can be formed starting from compound XI in the presence of pyridine-sulfur trioxide complex in pyridine at reflux temperature. The intermediate sulfonate may be chlorinated at reflux temperature in the presence of a chlorinating agent (e.g., triphenylphosphine/trichloroacetonitrile) in a solvent (e.g., dichloromethane).

Alternatively, some compounds of formula I are prepared by reacting a sulfonyl chloride of formula XII with an aniline of formula X according to the following formula:

the reaction can be carried out in the presence of a base (e.g., pyridine) as a solvent at room temperature.

Alternatively, some compounds of formula I may be prepared by deprotection of a compound of formula I-P, where P is a protecting group, e.g., phenylsulfonyl (PhSO), according to the following formula₂)：

Can be carried out in the presence of a weak base (such as potassium carbonate or cesium carbonate) in a mixture of polar solvents (such as methanol or di-ethanol)Alkane and water), the reaction is carried out at room temperature or, preferably, at a temperature of from 80 to 120 ℃ with heating. This reaction can be carried out in the presence of tetrabutylammonium fluoride in a solvent such as THF, with heating at a temperature preferably of from 60 to 90 ℃.

Compounds of formula I-P can be prepared by reacting a sulfonyl chloride of formula XII-P with an aniline of formula X. The reaction can be carried out in the presence of a base (e.g., pyridine) as a solvent at room temperature.

Compounds of formula XII can be prepared by chlorination of compounds of formula IX according to the following formula:

this reaction can be carried out in a polar solvent such as acetonitrile in the presence of a chlorinating agent such as phosphorus oxychloride at a temperature of 50 to 100 ℃.

A compound of formula IX wherein the compound of formula XI can be prepared according to the following formula:

this reaction can be carried out at reflux temperature in the presence of a base (e.g., pyridine) as a solvent, in the presence of a sulfonylating agent (e.g., pyridine-sulfur trioxide complex).

Compounds of formula XII-P can be prepared by chlorosulfonylation of compounds of formula XI-P, wherein P is a protecting group (e.g., phenylsulfonyl), according to the following formula:

the reaction can be carried out at room temperature in the presence of chlorosulfonic acid in a polar solvent such as acetonitrile.

Compounds of formula XI-P can be prepared by protection of compounds of formula XI, wherein P is a protecting group, such as benzenesulfonyl, according to the following formula:

this reaction can be carried out according to any method known to the person skilled in the art.

The anilines of formula X are commercially available or can be prepared according to any method known to those skilled in the art or using methods described in the literature. Alternatively, some anilines of formula X may be prepared by reduction of compound VIII according to the following formula:

this reaction can be carried out in the presence of an acid (e.g., acetic acid) or hydrogen, in the presence of a catalytic amount of Palladium on carbon (Palladium on charcoal), in a polar solvent (e.g., ethyl acetate or methanol), using any reducing agent (e.g., iron), or according to any method known to those skilled in the art.

The compounds of formula VIII are commercially available or can be prepared according to literature procedures or any other method known to those skilled in the art.

The compounds of formula XI are commercially available or may be prepared by suitable methods well known to those skilled in the art.

A-II. abbreviated/repeated reagents

Ac: acetyl group

ACN: acetonitrile

AcOH: acetic acid

Brine: saturated aqueous sodium chloride solution

Boc: tert-butoxycarbonyl group

nBu: n-butyl

tBu: tert-butyl radical

Cy: cyclohexyl radical

DAST: sulfur fluoride diethyl amino group

dba: dibenzylidene acetone (dibenzylidene aceteone)

DCM: methylene dichloride

DMAP: 4-dimethylaminopyridine

DMF: n, N-dimethylformamide

DMSO, DMSO: dimethyl sulfoxide (Dimethylsulfoxide)

Dppf: 1,1 '-bis (diphenylphosphino) ferrocene (1, 1' -bis (diphenylphosphinyl) ferrocene)

ES⁺: electrospray Ionization (Electrospray Ionization)

ES^-: electrospray Negative Ionization (Electrospray Ionization)

ESI: electrospray Ionization (Electrospray Ionization)

EtOAc: ethyl acetate

h: hour(s)

LC: liquid chromatography analysis

LCMS: liquid chromatography mass spectrometry

Me: methyl radical

MeOH: methanol

min.: minute (min)

mw: microwave oven

NBS: n-bromosuccinimide

NCS: n-chlorosuccinimide

NMR: nuclear magnetic resonance

rt: at room temperature

TBAHSA: tetrabutylammonium hydrogen sulfate

TBAF: tetrabutylammonium fluoride

TEA: triethylamine

TFAA: trifluoroacetic anhydride

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

Xantphos: 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (4,5-bis (diphenylphosphino) -9,9-dimethylxanthene)

A-III. analysis method

Commercial solvents and reagents are generally used without further purification, with anhydrous solvents (usually Sure-Seal from Aldrich Chemical Company) included as appropriate^TMProduct or Acroseal from ACROS Organics^TM). Typically, the reaction is followed by thin layer chromatography or liquid chromatography mass spectrometry.

Mass spectrometry measurements in LCMS mode were performed using different methods and instruments as follows:

basic LCMS method 1:

QDA Waters simple quadrupole mass spectrometer was used for LCMS analysis. The spectrometer was equipped with an ESI source and a UPLC acquisition Hclass with a diode array detector (200 to 400 nm). Data were obtained from a full MS scan of m/z 70 to 800 in positive/negative mode by basic elution (basic elution). Reverse phase separation was carried out at 45 ℃ on a Waters Acquity UPLC BEH C181.7 μm (2.1X 50mm) column for basic elution. The gradient elution was carried out with water/ACN/ammonium formate (95/5/63mg/L) (solvent A) and ACN/water/ammonium formate (95/5/63mg/L) (solvent B) according to Table 1. Injection amount: 1 μ L. And (4) MS full flow.

Table 1:

basic LCMS method 2:

mass Spectra (MS) spectra were recorded on an LCMS-2010EV mass spectrometer (Shimadzu) with electrospray ionization (ESI) coupled to an HPLC module promience (Shimadzu) using an Xbridge C18-2.1 × 30mm, 2.5 μm (waters) column. The volume of the injected sample solution was 3. mu.L, and the concentration was about 1 mg/mL. The mobile phase under alkaline conditions is a)5mM ammonium formate + 0.1% aqueous ammonia solution B) a mixture of 5% mobile phase a + 0.1% ammonia in acetonitrile solution. The gradient used was as follows: within 4 minutes 5: 95(B/A) to 95: 5(B/A) and for the next 1 minute a 95: 5 (B/A).

Neutral LCMS method 3:

the following procedure was used on LCMS instruments (Applied)

Mass Spectrometry (MS) spectra were recorded on Biosystems API 2000 LC/MS, HPLC Agilent 1100): in ACN (solvent a) or water (containing 2mM ammonium acetate): MeOH90:10 (solvent B) dissolved compound at a concentration of 1.0mg/mL and sonicated if necessary until completely dissolved. Then, 10. mu.L of the solution was injected into a Phenomenex Luna C18 HPLC column (50X 2.00mm, particle size 3 μm) and purified with water: ACN (gradient a) or water: MeOH (gradient B) was separated from 90:10 to 0: a gradient of 100 was run, the gradient was started after 1 minute, followed by elution in pure organic solvent at a flow rate of 300. mu.L/min for 10 minutes. UV absorption was detected from 220 to 400nm using a Diode Array Detector (DAD).

Acidic LCMS method 4:

performed on an Agilent 1200-6120 LC-MS system

HPLC-MS, Agilent 1200 & 6120 LC-MS System coupled to UV Detection (230 & 400nm & 215nm) and Mass Spec Detection Agilent 6120 Mass spectrometer (ES) M/z 120 to 800 using X-Bridge C18 Waters 2.1X 20mm, 2.5. mu.M column. Elution was carried out with a gradient as described in Table 2, mobile phase A (10mM ammonium formate in water + 0.1% formic acid) and mobile phase B (acetonitrile + 5% water + 0.1% formic acid) at a flow rate of 1 mL/min.

Table 2:

time (min)	A(％)	B(％)
			0	94	6
1.5	5	95
			2.25	5	95
2.50	94	6

The starting material can be purified by normal phase chromatography, (acidic or basic) reverse phase chromatography or recrystallization.

Normal phase chromatography using silica gel column (100: 200 mesh silica gel or cartridge for flash chromatography system) such asIsolera (K) of^TMFour or Teledyne Isco)。

Preparative reverse phase chromatography was performed with two different instruments and according to the following method:

basic preparation LCMS method 1:

LCMS purification MS detection was performed using SQD or QM Waters single quadrupole mass spectrometers. The spectrometer was equipped with an ESI source, a Waters 2525 binary pump coupled 2767 sample manager and a diode array detector (210 to 400 nm).

MS parameters: ESI capillary voltage 3 kV. Cone (cone) and extraction cone (extractor) voltages 10. The Source block (Source block) temperature was 120 ℃. The desolvation temperature was 300 ℃. Conical flow (Cone gaz flow)30L/h (nitrogen), desolvation flow 650L/h. Data is acquired from a full MS scan of m/z 100 to 850 in positive/negative mode.

LC parameters are as follows: reverse phase separation was carried out on an Xbridge prep OBD C18 column (5 μm, 30X 50mm) at room temperature. With solvent A1 (H)₂O+NH₄HCO₃ 10mM+50μl/L NH₄OH) and solvent B1 (100% ACN) (pH 8.5). HPLC flow rate: 35ml/min to 45ml/min, injection volume: 990. mu.l. The split ratio (splitting ratio) was set to +/-1/6000 to MS (Table 3).

Table 3:

time (min)	A1(％)	B1(％)	Flow rate (mL/min)
				0	95	5	35
1	95	5	35
				7	10	90	35
7.5	5	95	35
				9	5	95	35
9.1	5	95	45
				12	5	95	45

Neutral RP-HPLC method 2:

HPLC purification of the final product was performed on a Knauer Smartline 1050 HPLC system using an RP-HPLC column (Knauer 20mm i.d., Eurospher-100C 18). The product was dissolved in methanol (20mg/8mL) and subjected to reverse phase HPLC using a methanol/water (70: 30 to 100: 0 over 24 min) gradient.

NMR spectra were recorded on different instruments:

BRUKER AVANCEIII 400MHz-Ultrashield NMR spectrometer equipped with Windows 7 professional workstation running Topspin 3.2 software and 5mm dual resonance broadband probe (PABBI 1H/19F-BB Z-GRD Z82021/0075) or 1mm triple resonance probe (PATXI 1H/D-13C/15N Z-GRD Z868301/004).

-Varian 400MHz NMR spectrometer with acquisition time (at) 2.0 seconds, relaxation delay (d1) 2.0 seconds and line broadening (lb) 0.5 Hz.

-Bruker Avance DRX 500MHz NMR spectrometer

Bruker Avance III 600MHz NMR spectrometer

Chemical shift (Chemical shift) references were derived from deuterated solvents (DMSO-d)₆、Benzene-d₆Or CDCl₃) Signal of residual protons. Chemical shifts are expressed in parts per million (ppm) and coupling constants (J) in hertz (Hz). Spin multiplicities (Spin multiplicities) are expressed as broad (br), singlet(s), doublet (d), triplet (t), quadruplet (q) and multiplet (m).

The product is typically dried under vacuum prior to final analysis and submitted to biological testing.

A to IV: example Compounds and syntheses

The names of the following compounds are the IUPAC names generated by Biovia Draw Version 16.1 for intermediates of formula X, XI, XII and by Pipeline Pilot 2018 using OpenEye oemetache Version 1.4.5 for example compounds of formula I.

Intermediates

At the time of commercial purchase, the starting material is identified by its CAS registry number.

A. Synthesis of intermediates of formula X

A.1.2, 5-difluoropyridin-3-ylamine X-1 synthesis:

to a solution of 2, 5-difluoro-3-nitro-pyridine (0.30g, 1.87mmol) in EtOAc (40mL) was added Pd/C (0.13g, 1.27mmol) and the reaction mixture was stirred at room temperature under hydrogen pressure for 8 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite, washed with EtOAc (40mL) and the filtrate was concentrated in vacuo to give 2, 5-difluoropyridin-3-amine X-1(0.19g) as a yellow solid.

This compound was used in the next reaction without further purification.

Yield: 71 percent.

Basic LCMS method 2 (ES)⁺)：131(M+H)⁺90% purity.

¹H NMR(400MHz,DMSO-d₆)δ5.81(brs,2H)，6.94-6.98(m,1H)，7.23(t,J＝2.69Hz,1H)

A.2.6-chloro-2, 5-difluoro-pyridin-3-amine X-2 synthesis:

step 1: synthesis of 2, 5-difluoro-1-oxo-pyridin-1-ium (2, 5-difluoro-1-oxo-pyridin-1-ium) X-2 a:

to a solution of 2, 5-difluoropyridine (3.00g, 26.1mmol) in DCM (120mL) was added Urea hydrogen peroxide (7.36g, 78.2mmol), and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 ℃ and trifluoroacetic anhydride (12mL) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was washed with NaHCO₃Aqueous solution (120mL) was diluted and extracted with DCM (3X 80 mL). Separating the organic layer with anhydrous Na₂SO₄Drying and concentration in vacuo afforded 2, 5-difluoro-1-oxo-pyridin-1-ium X-2a (1.00g) as an off-white solid.

This compound was used in the next reaction without further purification.

Yield: 29 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.39-7.47(m,1H)，7.50(m,1H)，8.48-8.57(m,1H)。

Step 2: synthesis of 2-chloro-3, 6-difluoro-pyridine X-2 b:

to a solution of 2, 5-difluoro-1-oxo-pyridin-1-ium X-2a (0.95g, 7.25mmol) in DCM (30mL) at 0 deg.C was added POCl dropwise₃(1.33mL, 14.5 mmol). The reaction mixture was stirred at the same temperature for 5 minutes, and then DMF (0.60mL) was added.The reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, saturated NaHCO was used₃The reaction mixture was quenched (queue) with a solution (50mL) and extracted with EtOAc (2X 50 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2-chloro-3, 6-difluoro-pyridine X-2b (0.65g) as a light brown liquid. This compound was used in the next reaction without further purification.

Yield: 60 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.35-7.39(m,1H)，8.15-8.23(m,1H)。

And step 3: synthesis of 2-chloro-3, 6-difluoro-5-nitro-pyridine X-2 c:

to a solution of 2-chloro-3, 6-difluoro-pyridine X-2b (0.60g, 4.01mmol) in fuming HNO₃(4.19mL, 100mmol) of concentrated H₂SO₄(3.21mL, 60.2mmol) the temperature was maintained below 40 ℃. The reaction mixture was then heated at 60 ℃ for 30 minutes. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled and poured into crushed ice and extracted with DCM (2 × 50 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo. The crude product obtained was purified by column chromatography (100-mesh 200-mesh, 10% EtOAc in hexane) to give 2-chloro-3, 6-difluoro-5-nitro-pyridine X-2c (0.185g) as a pale yellow liquid.

Yield: 24 percent.

¹H NMR(400MHz,DMSO-d₆)δ9.10-9.14(m,1H)。

And 4, step 4: synthesis of 6-chloro-2, 5-difluoro-pyridin-3-amine X-2:

to a solution of 2-chloro-3, 6-difluoro-5-nitro-pyridine X-2c (0.18g, 0.93mmol) in acetic acid (9mL) was added iron (0.05g, 0.93mmol) and the reaction mixture was heated at 80 ℃ for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo. The residue was diluted with EtOAc (40mL) and saturated NaHCO₃(25mL) was washed. Separating the organic layer with anhydrous Na₂SO₄Drying and vacuum concentrating to obtain 6-chloro-2, 5-diFluoro-pyridin-3-amine X-2(0.28g) as a light brown solid.

This compound was used in the next reaction without further purification.

Yield: 42 percent.

Basic LCMS method 2 (ES)^-)：163(M-H)^-23% purity.

A.3.6-chloro-5-fluoro-2-methoxy-pyridin-3-amine X-3 Synthesis:

step 1: synthesis of 2-chloro-3-fluoro-6-methoxy-5-nitro-pyridine X-3 a:

to a solution of 2-chloro-3, 6-difluoro-5-nitro-pyridine X-2c (0.67g,3.44mmol) in MeOH (10mL) at-40 deg.C was added NaOMe (0.82mL, 3.79mmol) dropwise and the reaction mixture was stirred at the same temperature for 20 min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold 1N HCl (10mL) and extracted with hexane (2 × 15 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2-chloro-3-fluoro-6-methoxy-5-nitro-pyridine X-3a (0.40g) as a yellow solid.

This compound was used in the next reaction without further purification.

Yield: 56 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.03(s,3H)，8.82(d,J＝7.83Hz,1H)。

Step 2: synthesis of 6-chloro-5-fluoro-2-methoxy-pyridin-3-amine X-3:

to a stirred solution of 2-chloro-3-fluoro-6-methoxy-5-nitro-pyridine X-3a (0.20g, 0.97mmol) in acetic acid (4mL) at 0 deg.C was added iron (0.22g, 3.87 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold saturated NaHCO₃(25 mL). The reaction mixture was filtered through a pad of celite, washed with EtOAc (2 × 15mL) and the aqueous layer was extracted with EtOAc (2 × 15 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 4% EtOAc in hexane) to afford 6-chloro-5-fluoro-2-methoxy-pyridin-3-amine X-3(0.11g, 63%) as an off-white solid.

Yield: and 63 percent.

Basic LCMS method 2 (ES)⁺)：177(M+H)⁺And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.84(s,3H)，5.49(brs,2H)，6.90(d,J＝9.78Hz,1H)。

A.4.6-chloro-2-fluoro-5-methoxy-pyridin-3-amine X-4 Synthesis:

step 1: synthesis of 3-bromo-2-fluoro-5-methoxy-pyridine X-4 a:

to a solution of 5-bromo-6-fluoro-pyridin-3-ol (0.80g, 4.17mmol) and NaH (0.33g, 8.33mmol) in DMF (15mL) was added CH dropwise at 0 deg.C₃I (0.31mL,5.00 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into cold H₂O (20mL) and extracted with EtOAc (2X 30 mL). The organic layer was separated, washed with brine (20mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The resulting crude product was purified by combined flash column chromatography (30% EtOAc in hexanes) to give 3-bromo-2-fluoro-5-methoxy-pyridine X-4a (0.80g) as a light yellow solid.

Yield: 93 percent.

Basic LCMS method 2 (ES)⁺)：206(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.85(s,3H)，7.92(t,J＝2.20Hz,1H)，7.99(dd,J＝7.34,2.20Hz,1H)。

Step 2: synthesis of 3-bromo-2-fluoro-5-methoxy-1-oxo-pyridin-1-ium X-4 b:

to the solution at 0 deg.C in the presence of 3-bromo-2-fluoro-5-methoxy-pyridine X-4a (0.30g, 1.35 m)mol) to a solution of DCM (15mL) was added carbamide peroxide (0.38g, 4.05mmol) and the reaction mixture was stirred for 10 min. Trifluoroacetic anhydride (0.96mL, 6.76mmol) was added dropwise at 0 deg.C and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold H₂In O (15mL), saturated NaHCO is used₃Basified to pH 8(15 mL) and extracted with DCM (2X 15 mL). The organic layer was separated, washed with brine (10mL), and dried over anhydrous Na₂SO₄Dried and concentrated in vacuo to give 3-bromo-2-fluoro-5-methoxy-1-oxo-pyridin-1-ium (3-bromo-2-fluoro-5-methoxy-1-oxido-pyridine-1-ium) X-4b (0.16g, 37%) as an off-white solid.

This compound was used in the next reaction without further purification.

Yield: 93 percent.

Basic LCMS method 2 (ES)⁺)：222(M+H)⁺And 69% purity.

And step 3: synthesis of 5-bromo-2-chloro-6-fluoro-3-methoxy-pyridine X4-c:

to a solution of 3-bromo-2-fluoro-5-methoxy-1-oxo-pyridin-1-ium X-4b (0.40g, 1.45mmol) in DCM (10mL) at 0 deg.C was added POCl₃(0.35mL, 3.88mmol) was then added DMF (0.1mL) and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum. The residue was poured into ice-cold H₂In O (15mL), saturated NaHCO is used₃Basified to pH 8(15 mL) and extracted with EtOAc (2X 15 mL). The organic layer was separated, washed with brine (15mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by combined flash column chromatography (30% EtOAc in hexanes) to afford 5-bromo-2-chloro-6-fluoro-3-methoxy-pyridine X4-c (0.26g) as a light yellow solid.

Yield: 74 percent.

¹H NMR(400MHz,DMSO-d₆)δ3.93(s,3H)，8.16(d,J＝6.85Hz,1H)。

And 4, step 4: synthesis of N- (6-chloro-2-fluoro-5-methoxy-3-pyridyl) -1, 1-diphenyl-azomethine X4-d:

to a solution of bis (0.25g, 1.04mmol) of 5-bromo-2-chloro-6-fluoro-3-methoxy-pyridine X4-c and benzophenone imine (0.21g, 1.14mmol)Adding Cs to an alkane (15mL) solution₂CO₃(1.02g, 3.12mmol) and 4,5-bis diphenylphosphine-9, 9-dimethylxanthene (Xantphos) (0.12g, 0.21 mmol). The reaction mixture was purged with argon for 20 minutes, followed by the addition of Pd₂(dba)₃(0.10g, 0.10 mmol). The reaction mixture was heated at 100 ℃ for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with EtOAc (15mL), filtered through a pad of Celite and washed with EtOAc (2X 15 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by combined flash column chromatography (30% EtOAc in hexanes) to afford N- (6-chloro-2-fluoro-5-methoxy-3-pyridyl) -1, 1-diphenyl-azomethine X4-d (0.25g, 50%) as an off-white solid.

Yield: 93 percent.

Basic LCMS method 2 (ES)⁺)：341(M+H)⁺71% purity.

And 5: synthesis of 6-chloro-2-fluoro-5-methoxy-pyridin-3-amine X-4:

to a solution of N- (6-chloro-2-fluoro-5-methoxy-3-pyridyl) -1, 1-diphenyl-azomethine X4-d (0.24g, 0.51mmol) in MeOH (15mL) at 0 deg.C was added 1N HCl (0.5 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into H₂O (15mL) and extracted with DCM (2X 20 mL). The organic layer was separated, washed with brine (20mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by combined flash column chromatography (30% EtOAc in hexanes) to afford 6-chloro-2-fluoro-5-methoxy-pyridin-3-amine X-4(0.06g) as an off-white solid.

Yield: 62 percent.

Basic LCMS method 2 (ES)⁺)：177(M+H)⁺And 93% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.79(s,3H)，5.64(s,2H)，6.99(d,J＝8.80Hz,1H)

A.5.synthesis of 2, 5-difluoro-6-methoxy-pyridin-3-amine X-5:

step 1: synthesis of 2,3, 6-trifluoro-5-nitro-pyridine X-5 a:

to a stirred solution of 2,3, 6-trifluoropyridine (2.00g, 15.0mmol) in fuming HNO at 0 deg.C₃(12.5mL, 301mmol) of the solution concentrated H was added dropwise₂SO₄(12.0mL, 225 mmol). The reaction mixture was heated at 60 ℃ for 1 hour. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured onto crushed ice (40mL) and extracted with hexane (2X 30 mL). The organic layer was separated and washed with saturated NaHCO₃(40mL) washing with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2,3, 6-trifluoro-5-nitro-pyridine X-5a (1.20g) as a yellow oil.

This compound was used in the next reaction without further purification.

Yield: 45 percent.

¹H NMR(400MHz,DMSO-d₆)δ9.20-9.26(m,2H)。

Step 2: synthesis of 2, 5-difluoro-6-methoxy-3-nitro-pyridine X-5 b:

to a stirred solution of 2,3, 6-trifluoro-5-nitro-pyridine X-5a (0.20g, 1.12mmol) in MeOH (10mL) at-78 deg.C was added NaOMe (0.93mL, 4.32mmol) dropwise and the reaction mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with saturated HCl (10mL) at-78 ℃ and extracted with hexane (2X 15 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2, 5-difluoro-6-methoxy-3-nitro-pyridine X-5b (0.136g) as a pale yellow solid.

This compound was used in the next reaction without further purification.

Yield: and 64 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.06(s,3H)，8.76(dd,J＝8.80,7.34Hz,1H)。

And step 3: synthesis of 2, 5-difluoro-6-methoxy-pyridin-3-amine X-5:

to a stirred solution of 2, 5-difluoro-6-methoxy-3-nitro-pyridine X-5b (0.13g, 0.68mmol) in acetic acid (4mL) was added iron (0.15g, 2.74mmol) portionwise at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion, saturated NaHCO was used₃The reaction mixture was quenched (25mL) and extracted with EtOAc (2X 25 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to afford 2, 5-difluoro-6-methoxy-pyridin-3-amine X-5(0.104g, 94%) as a brown solid.

This compound was used in the next reaction without further purification.

Yield: 62 percent.

Basic LCMS method 2 (ES)⁺)：161(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.77(s,3H)，5.04(brs,2H)，7.17(dd,J＝10.76,8.31,1H)。

A.6.6 Synthesis of 5-fluoro-2, 6-dimethoxy-pyridin-3-amine X-6:

step 1: synthesis of 3-fluoro-2, 6-dimethoxy-5-nitro-pyridine X-6 a:

to a stirred solution of 2,3, 6-trifluoro-5-nitro-pyridine X-5a (0.30g, 1.68mmol) in MeOH (4mL) at-40 deg.C was added NaOMe (0.36mL, 1.68mmol) dropwise and the reaction mixture was stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with 2N HCl (6mL) at 0 ℃ and extracted with hexane (2X 10 mL). Separating the organic layer with anhydrous Na₂SO₄Drying and curingEvaporation was carried out under air to obtain 3-fluoro-2, 6-dimethoxy-5-nitro-pyridine X-6a (0.32g, 94%) as a pale yellow solid.

This compound was used in the next reaction without further purification.

Yield: 94 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.06(s,3H)，4.09(s,3H)，8.52(d,J＝9.29Hz,1H)。

Step 2: synthesis of 5-fluoro-2, 6-dimethoxy-pyridin-3-amine X-6:

to a stirred solution of 3-fluoro-2, 6-dimethoxy-5-nitro-pyridine X-6a (0.25g, 1.24mmol) in acetic acid (8mL) was added iron (0.28g, 4.95mmol) portionwise at 0 ℃. The reaction mixture was stirred at room temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold saturated NaHCO₃(25mL) and extracted with EtOAc (2X 20 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 5-fluoro-2, 6-dimethoxy-pyridin-3-amine X-6(0.19g) as a brown solid.

This compound was used in the next reaction without further purification.

Yield: 89 percent.

Basic LCMS method 2 (ES)⁺)：173(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.82(s,3H)，3.85(s,3H)，4.58(brs,2H)，6.92(d,J＝11.25Hz,1H)。

A.7.synthesis of 2, 5-difluoro-6-methyl-pyridin-3-amine X-7:

di-chloro-2, 5-difluoro-pyridin-3-amine X-2(0.24g, 1.38mmol) at room temperatureTo a solution of alkane (12mL) was added methylboronic acid (0.25g, 4.15mmol) and Cs₂CO₃(1.13g,3.46mmol) of H₂O (4mL) solution and the reaction mixture purged with argon for 20 min. Adding PdCl₂(dppf) (0.10g,0.14mmol) and the reaction mixture purged with argon for 10 minutes. The reaction mixture was heated at 120 ℃ for 6 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature, filtered through a pad of celite, washed with EtOAc (2 × 60mL), and the filtrate was concentrated in vacuo. The residue is washed with H₂O (60mL) was diluted and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (70mL), and dried over anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2, 5-difluoro-6-methyl-pyridin-3-amine X-7(0.32g) as a light brown liquid.

This compound was used in the next reaction without further purification.

Yield: 51 percent.

Basic LCMS method 2 (ES)⁺)：145(M+H)⁺And 31% purity.

A.8.synthesis of 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-amine X-8:

step 1: synthesis of 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol X-8 a:

to a solution of 2-chloro-3-fluoro-6-methoxy-5-nitro-pyridine X-3a (0.90g, 4.36mmol) in H₂To a solution of O (6mL) was added KOH (0.61g, 10.9mmol) and the reaction mixture was heated at 80 ℃ for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture is washed with H₂O (100mL) was diluted and extracted with EtOAc (3X 80 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol X-8a (0.30g crude product) as a pale yellow solid.

This compound was used in the next reaction without further purification.

¹H NMR(400MHz,DMSO-d₆)δ3.99(s,3H)，8.42(d,J＝9.60Hz,1H)，12.12(s,1H)。

Step 2: synthesis of 2- (difluoromethoxy) -3-fluoro-6-methoxy-5-nitro-pyridine X-8 b:

to CH with 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol X-8a (0.29g, 1.54mmol) at 40 deg.C₃CN (4mL) solution was added KOH (0.87g, 15.4mmol) in H₂O (1mL) solution and bromodifluoromethyl diethylphosphonate (2.74mL, 15.4mmol), the reaction mixture was stirred at the same temperature for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture is washed with H₂O (50mL) was diluted and extracted with EtOAc (3X 40 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The resulting crude product was purified by flash chromatography (2 to 5% EtOAc in hexanes) to give 2- (difluoromethoxy) -3-fluoro-6-methoxy-5-nitro-pyridine X-8b (0.24g) as a light yellow liquid.

This compound was used in the next reaction without further purification.

Yield: 65 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.04(s,3H)，7.90(t,J＝70.8Hz,1H)，8.80(d,J＝9.60Hz,1H)。

And step 3: synthesis of 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-amine X-8:

to CH with 2- (difluoromethoxy) -3-fluoro-6-methoxy-5-nitro-pyridinX-8 b (0.23g, 0.97mmol) at 0 deg.C₃To the COOH (8mL) solution was added Fe (0.27g, 4.83mmol) slowly and the reaction mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of celite, washed with EtOAc (80mL), and the filtrate was concentrated in vacuo. The residue was poured into saturated NaHCO₃(80mL) in aqueous solution and extracted with EtOAc (2X 70 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-amine X-8(0.18g) as a brown liquid.

This compound was used in the next reaction without further purification.

Yield: 77 percent.

Basic LCMS method 2 (ES)^-)：207(M-H)^-And 85% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.84(s,3H)，5.18(brs,2H)，6.95(d,J＝10.8Hz,1H)，7.39(t,J＝74Hz,1H)。

A.9.5-bromo-3-methoxypyrazine-2-amine X-9:

step 1: synthesis of 3, 5-dibromopyrazine-2-amine X-9 a:

DMSO (10mL) with pyrazin-2-amine (0.50g,5.26mmol) and H were added in 10 min at 15 deg.C₂NBS (1.97g, 11.0mmol) was added portionwise to a solution of O (0.3 mL). The reaction was stirred at room temperature in the absence of light for 5 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold H₂O (60mL) and extracted with EtOAc (2X 70 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The resulting crude product was purified by column chromatography (silica, 100 mesh, 200 mesh, 5% EtOAc in hexanes) to afford 3, 5-dibromopyrazin-2-amine X-9a (0.612g) as an off-white solid.

Yield: 46 percent.

Basic LCMS method 2 (ES)⁺)：252(M+H)⁺100% purity.

¹H NMR(400MHz,DMSO-d₆)δ6.97(brs,2H)，8.13(s,1H)。

Step 2: synthesis of 5-bromo-3-methoxy-pyrazin-2-amine X-9:

a solution of 3, 5-dibromopyrazin-2-amine X-9a (0.60g,2.37mmol) and NaOMe (0.15g,2.78mmol) in MeOH (15mL) was heated at reflux for 1 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature. The precipitated solid was purified by column chromatography (silica, 100 mesh, 200 mesh, 10% EtOAc in hexane) to obtain 5-bromo-3-methoxy-pyrazin-2-amine X-9(0.295g) as a white solid.

Yield: 61 percent.

Basic LCMS method 2 (ES)⁺)：204(M+H)⁺100% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.87(s,3H)，6.52(brs,2H)，7.57(s,1H)

A.10.5-chloro-3-methoxypyrazin-2-amine X-10 synthesis:

step 1: 3, synthesis of 5-dichloropyrazin-2-amine X-10 a:

to a stirred solution of pyrazin-2-amine (2.00g, 21.0mmol) in CHCl₃To the solution (25mL) was added NCS (3.65g, 27.3mmol) in portions, and the reaction mixture was stirred at room temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold H₂O (20mL) and extracted with EtOAc (2X 40 mL). The organic layer was separated, washed with brine (25mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by combined flash chromatography (20% EtOAc in hexanes) to afford 3, 5-dichloropyrazin-2-amine X-10a (1.50g) as an off-white solid.

Yield: 37 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.02(brs,2H)，8.06(s,1H)。

Step 2: synthesis of 5-chloro-3-methoxypyrazine-2-amine X-10:

to a stirred solution of 3, 5-dichloropyrazin-2-amine X-10a (0.80g,4.15mmol) in MeOH (20mL) at room temperature was added NaOMe (0.90g, 16.6 mmol). The reaction mixture was heated at 70 ℃ for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum. The residue is washed with H₂O (15mL) was diluted and extracted with EtOAc (3X 25 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The obtained crude product is passed through a combination blockPurification by flash chromatography (20% EtOAc in hexanes) afforded 5-chloro-3-methoxypyrazin-2-amine X-10(0.53g) as an off-white solid.

Yield: and 69 percent.

¹H NMR(400MHz,DMSO-d₆)δ3.89(s,3H)，6.52(brs,2H)，7.53(s,1H)。

A.11.synthesis of 5-fluoro-6- (2-fluoroethoxy) -2-methoxy-pyridin-3-amine X-11:

step 1: synthesis of 2, 5-difluoro-6- (2-fluoroethoxy) -3-nitropyridine X-11 a:

to a stirred solution of 2-fluoroethanol (1.19g, 18.5mmol) in THF (30mL) at 0 deg.C was added NaH (0.81g, 20.2mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to-78 ℃ and then 2,3, 6-trifluoro-5-nitro-pyridine X-5a (3.00g, 16.8mmol) was added slowly at the same temperature and the reaction mixture was stirred at-78 ℃ for 2 hours. The progress of the reaction was monitored by TLC. After completion, with ice cold H₂The reaction mixture was quenched with O (50mL) and extracted with EtOAc (2X 100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2, 5-difluoro-6- (2-fluoroethoxy) -3-nitropyridine X-11a (3.10g) as a brown gummy liquid.

This compound was used in the next reaction without further purification.

Yield: 83 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.64-4.69(m,1H)4.73-4.76(m,2H)4.86-4.89(m,1H)8.79-8.83(m,1H)。

Step 2: synthesis of 2, 5-difluoro-6- (2-fluoroethoxy) pyridin-3-amine X-11 b:

to CH of 2, 5-difluoro-6- (2-fluoroethoxy) -3-nitropyridine X-11a (2.70g, 12.2mmol) at 0 deg.C₃To the COOH (25mL) solution was added Fe (6.79g, 122mmol) and the reaction mixture was stirred at room temperature for 2 h. Monitoring by TLC and LCMSAnd (4) reaction progress. After completion, the reaction mixture was filtered through a pad of celite and Et₂O (500mL) rinse, and the filtrate was concentrated in vacuo. The residue was poured into saturated NaHCO₃In aqueous solution (380mL) and with Et₂O (2X 500 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2, 5-difluoro-6- (2-fluoroethoxy) pyridin-3-amine X-11b (2.00g) as a brown solid.

This compound was used in the next reaction without further purification.

Yield: 70 percent.

Basic LCMS method 2 (ES)⁺)：193(M+H)⁺And 82% purity.

And step 3: synthesis of 5-fluoro-6- (2-fluoroethoxy) -2-methoxy-pyridin-3-amine X-11

To a solution of 2, 5-difluoro-6- (2-fluoroethoxy) pyridin-3-amine X-11b (1.00g,4.27mmol) in MeOH (10mL) at 0 deg.C was slowly added NaOMe (25% in MeOH, 1.85mL, 8.55mmol) and the reaction mixture was heated at 100 deg.C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was quenched with ice-cold 1N aqueous HCl (50mL) and extracted with hexane (2 × 500 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by preparative HPLC to give 5-fluoro-6- (2-fluoroethoxy) -2-methoxy-pyridin-3-amine X-11(0.46g) as a brown solid.

Yield: 50 percent.

Basic LCMS method 2 (ES)⁺)：205(M+H)⁺And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.83(s,3H)4.41-4.43(m,1H)4.48-4.50(m,1H)4.65(brs,3H)4.76-4.78(m,1H)6.90-6.98(m,1H)。

A.12.Synthesis of 6- (2-fluoroethoxy) -2-methoxypyridin-3-amine X-12:

step 1: synthesis of 2, 6-difluoro-3-nitropyridine X-12 a:

to concentrated HNO with 2, 6-difluoropyridine (5.00g,43.4mmol) at 0 deg.C₃(36.3mL,869mmol) of solution concentrated H was added slowly₂SO₄(34.7mL, 652mmol) and the reaction mixture was heated to 60 ℃ for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature, poured into crushed ice (120mL) and extracted with DCM (2 × 100 mL). The organic layer was separated and washed with saturated NaHCO₃Aqueous solution (120mL) and washed with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2, 6-difluoro-3-nitropyridine X-12a (3.20g crude) as a yellow oil.

This compound was used in the next reaction without further purification.

¹H NMR(400MHz,DMSO-d₆)δ7.47(dd,J＝8.80,2.45Hz,1H)8.91-9.00(m,1H)。

Step 2: synthesis of 6-fluoro-2-methoxy-3-nitropyridine X-12b and 2-fluoro-6-methoxy-3-nitropyridine X-12 c:

to a solution of 2, 6-difluoro-3-nitropyridine X-12a (2.90g, 18.1mmol) in THF (25mL) at-78 deg.C was added NaOMe (25% MeOH solution, 4.31mL, 19.9mmol) slowly and the reaction mixture was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion, with ice cold H₂The reaction mixture was quenched O (60mL) and Et₂O (2X 100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to afford 6-fluoro-2-methoxy-3-nitropyridine X-12b and 2-fluoro-6-methoxy-3-nitropyridine X-12c (2.51g, a mixture of two regioisomers) as a brown liquid.

This compound was used in the next reaction without further purification.

¹H NMR(400MHz,DMSO-d₆,¹H NMR showed mixture of regioisomers) δ 3.97(s,3H), 4.02(s,3H)6.97-7.00(m,2H)8.58-8.71(m, 2H).

And step 3: synthesis of 6- (2-fluoroethoxy) -2-methoxy-3-nitropyridine X-12d and 2- (2-fluoroethoxy) -6-methoxy-3-nitropyridine X-12 e:

to a solution of 2-fluoroethanol (1.12g, 17.5mmol) in DMF (40mL) was added Cs₂CO₃(9.51g, 29.2mmol) and a mixture of 6-fluoro-2-methoxy-3-nitropyridine X-12b and 2-fluoro-6-methoxy-3-nitropyridine X-12c (2.51g, 14.6mmol, a mixture of the two regioisomers). The reaction mixture was heated at 100 ℃ for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with cold H₂O (80mL) was diluted and extracted with EtOAc (2X 80 mL). Separating the organic layer with cold H₂O (2X 50mL) and Na anhydrous₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 5 to 12% EtOAc in hexane) and re-purified by preparative HPLC to afford 6- (2-fluoroethoxy) -2-methoxy-3-nitropyridine X-12d (0.98g) as an off-white solid and 2- (2-fluoroethoxy) -6-methoxy-3-nitropyridine X-12e (1.10g) as an off-white solid.

6- (2-fluoroethoxy) -2-methoxy-3-nitropyridine X-12 d:

yield: 31 percent.

¹H NMR(400MHz,CDCl₃)δ4.12(s,3H)4.63(t,J＝4Hz,1H)4.69-4.74(m,2H)4.84(t,J＝4Hz,1H)6.47(d,J＝8.8Hz,1H)8.39(d,J＝8.8Hz,1H)。

2- (2-fluoroethoxy) -6-methoxy-3-nitropyridine X-12 e:

yield: 35 percent.

¹H NMR(400MHz,CDCl₃)δ4.01(s,3H)4.75-4.78(m,2H)4.80-4.84(m,1H)4.85-4.91(m,1H)6.43(d,J＝8.8Hz,1H)8.37(d,J＝8.8Hz,1H)

And 4, step 4: synthesis of 6- (2-fluoroethoxy) -2-methoxypyridin-3-amine X-12:

to a solution of 6- (2-fluoroethoxy) -2-methoxy-3-nitropyridine X-12d (0.97g,4.49mmol) in CH₃To the COOH (15mL) solution was added Fe (1.25g, 22.4mmol) slowly and the reaction mixture was stirred at room temperature for 6 hours. The reaction progress was monitored by TLC and LCMS. Passing the reaction mixture through siliconThe celite pad was filtered, washed with EtOAc (80mL), and the filtrate was concentrated in vacuo. The residue was taken up in saturated NaHCO₃The solution (150mL) was diluted and extracted with EtOAc (2X 100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by flash chromatography (10 to 20% EtOAc in hexanes) to give 6- (2-fluoroethoxy) -2-methoxypyridin-3-amine X-12(0.67g) as a light brown liquid.

Yield: 79 percent.

Basic LCMS method 2 (ES)⁺)：187(M+H)⁺And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.84(s,3H)4.28-4.34(m,1H)4.36(s,2H)4.38-4.41(m,1H)4.62-4.66(m,1H)4.73-4.80(m,1H)6.20(d,J＝8.31Hz,1H)6.96(d,J＝7.83Hz,1H)。

A.13.synthesis of 2, 5-difluoro-6-methoxy-pyridin-3-amine X-13:

step 1: synthesis of 2- (2, 2-difluoroethoxy) -3, 6-difluoro-5-nitro-pyridine X-13 a:

to a stirred solution of 2, 2-difluoroethanol (0.79g, 11.2mmol) in THF (20mL) at 0 deg.C was added NaH (1.35g, 33.7mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to-78 ℃, then 2,3, 6-trifluoro-5-nitro-pyrx-5 a (2.00g, 11.2mmol) was added slowly at the same temperature and the reaction mixture was stirred at-78 ℃ for 2 hours. The progress of the reaction was monitored by TLC. After completion, with ice cold H₂The reaction mixture was quenched with O (50mL) and extracted with EtOAc (2X 100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude material was purified by column chromatography (silica, 100 mesh, 2% EtOAc in hexane) to give 2- (2, 2-difluoroethoxy) -3, 6-difluoro-5-nitro-pyridine X-13a (0.86g) as a brown liquid.

Yield: 32 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.78(td,J＝14.92,2.93Hz,2H)，6.32-6.62(m,1H)，8.87(dd,J＝8.80,7.34Hz,1H)

Step 2: synthesis of 6- (2, 2-difluoroethoxy) -2, 5-difluoro-pyridin-3-amine X-13:

to CH with 2- (2, 2-difluoroethoxy) 3, 6-difluoro-5-nitro-pyridine X-13a (0.85g, 3.5mmol) at 0 deg.C₃To the COOH (17mL) solution was added Fe (1.98g, 35mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of celite and Et₂O (500mL) rinse and the filtrate concentrated in vacuo. The residue was poured into saturated NaHCO₃In aqueous solution (380mL) and with Et₂O (2X 500 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude material was washed with pentane to give 6- (2, 2-difluoroethoxy) -2, 5-difluoro-pyridin-3-amine X-13(0.51g) as a brown solid.

This compound was used in the next reaction without further purification.

Yield: 67%.

Basic LCMS method 2 (ES)⁺)：211(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ4.43(td,J＝14.92,3.42Hz,2H)，5.20(s,2H)，6.20-6.50(m,1H)，7.21(dd,J＝10.76,8.31Hz,1H)。

A.14.synthesis of 6- (difluoromethoxy) -2-methoxy-pyridin-3-amine X-14:

step 1: synthesis of 6-methoxy-5-nitro-pyridin-2-ol X-14a and 6-methoxy-3-nitro-pyridin-2-ol X-14 b:

to a solution of a mixture of 6-fluoro-2-methoxy-3-nitropyridine X-12b and 2-fluoro-6-methoxy-3-nitropyridine X-12c (0.60g, 3.5mmol, a mixture of the two regioisomers) in water (20mL) was added KOH (0.78g, 13.9 mmol). The reaction mixture was heated at 60 ℃ for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0 ℃ and acidified to pH 4-5 with 1N HCl (6 mL). The precipitated solid was filtered and dried under vacuum to obtain a mixture of 6-methoxy-5-nitro-pyridin-2-ol X-14a and 6-methoxy-3-nitro-pyridin-2-ol X-14b (0.45g, a mixture of the two regioisomers) as a yellow solid.

Yield: 29 percent.

Basic LCMS method 2 (ES)⁺)：171(M+H)⁺99% purity (40/60 mixture).

Step 2: synthesis of 6- (difluoromethoxy) -2-methoxy-3-nitro-pyridine X-14c and 2- (difluoromethoxy) -6-methoxy-3-nitro-pyridine X-14 d:

to a solution (1.2g, 5.06mmol, mixture of two regioisomers) of a mixture of 6-methoxy-5-nitro-pyridin-2-ol X-14a and 6-methoxy-3-nitro-pyridin-2-ol X-14b in CH₃CN (32mL) and water (8mL) were added KOH (1.42g,25.3mmol) and diethylphosphonic acid bromodifluoromethyl ester (6.75g, 25.3mmol) and the reaction mixture was stirred at 60 ℃ for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture is washed with H₂O (60mL) was diluted and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (2X 50mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by flash chromatography (2% EtOAc in hexanes) to give 6- (difluoromethoxy) -2-methoxy-3-nitro-pyridine X-14c (0.24g) and 2- (difluoromethoxy) -6-methoxy-3-nitro-pyridine X-14d (0.07g) as an off-white solid.

6- (Difluoromethoxy) -2-methoxy-3-nitro-pyridine X-14c

Yield: 22 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.12(s,3H)，6.60(d,J＝8.80Hz,1H)，7.41(t,J＝72Hz,1H)，8.47(d,J＝8.80Hz,1H)。

2- (Difluoromethoxy) -6-methoxy-3-nitro-pyridine X-14d

Yield: 7 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.03(s,3H)，6.65(d,J＝9.29Hz,1H)，7.51(t,J＝72Hz,1H)，8.41(d,J＝9.29Hz,1H)。

And step 3: synthesis of 6- (difluoromethoxy) -2-methoxy-pyridin-3-amine X-14:

to a solution of 6- (2-fluoroethoxy) -2-methoxy-3-nitropyridine X-12d (50mg,0.22mmol) in MeOH (3mL) was added Pd/C (10mg) and the reaction mixture was stirred at room temperature under hydrogen pressure for 2 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite, washed with MeOH (2 × 30mL), and the filtrate was concentrated in vacuo to afford 6- (difluoromethoxy) -2-methoxy-pyridin-3-amine X-14(30mg) as a brown liquid.

This compound was used in the next reaction without further purification.

Yield: 68 percent.

Basic LCMS method 2 (ES)⁺)：191(M+H)⁺And 97% purity.

A.15.Synthesis of 6-chloro-4-methoxy-pyridin-3-amine X-15:

to CH with 2-chloro-4-methoxy-5-nitro-pyridine (2.0g,10.6mmol) at 0 deg.C₃To the COOH (15mL) solution was added Fe (2.96g,53mmol) and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of celite and washed with EtOAc (2 × 30mL), and the filtrate was concentrated in vacuo. The residue was poured into saturated NaHCO₃Aqueous (100mL) and extracted with EtOAc (2X 60 mL). Separating the organic layer with Na-free₂SO₄Dried and concentrated under vacuum. The crude material was washed with ether to give 6-chloro-4-methoxy-pyridin-3-amine X-15(0.95g) as an off-white solid.

Yield: and 55 percent.

Basic LCMS method 2 (ES)⁺)：159(M+H)⁺100% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.85(s,3H)，5.01(s,2H)，6.88(s,1H)，7.60(s,1H)。

A.16.Synthesis of 6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-amine X-16 and 2- (2, 2-difluoroethoxy) -6-methoxypyridin-3-amine X-17:

step 1: synthesis of 6- (2, 2-difluoroethoxy) -2-methoxy-3-nitropyridine X-16a and 2- (2, 2-difluoroethoxy) -6-methoxy-3-nitropyridine X-17 a:

to a solution of a mixture of 6-fluoro-2-methoxy-3-nitropyridine X-12b and 2-fluoro-6-methoxy-3-nitropyridine X-12c (4.00g, 23.2mmol, a mixture of the two regioisomers) in DMF (40mL) at 0 deg.C was added Cs₂CO₃(15.1g, 46.5mmol) and 2-fluoroethanol (1.79g, 27.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was taken up in ice-cold H₂O (50mL) was quenched and extracted with EtOAc (2X 300 mL). Separating the organic layer with Na-free₂SO₄Dried and concentrated in vacuo to afford 6- (2, 2-difluoroethoxy) -2-methoxy-3-nitropyridine X-16a and 2- (2, 2-difluoroethoxy) -6-methoxy-3-nitropyridine X-17a (4.20g of crude product, mixture of two regioisomers) as a brown gummy liquid.

¹H NMR (400MHz, DMSO-d6,1H NMR shows mixture of regioisomers) δ 3.99(s,3H)4.69-4.76(m,2H)6.64-6.68(m,1H)8.46(d, J ═ 3.91Hz,1H)8.48(d, J ═ 3.91Hz, 1H).

Step 2: synthesis of 6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-amine X-16 and 2- (2, 2-difluoroethoxy) -6-methoxypyridin-3-amine X-17:

to CH with 6- (2, 2-difluoroethoxy) -2-methoxy-3-nitropyridine X-16a and 2- (2, 2-difluoroethoxy) -6-methoxy-3-nitropyridine X-17a (0.50g, 2.14mmol, mixture of two regioisomers) at 0 deg.C₃COOHTo the solution (10mL) iron (1.19g, 21.4mmol) was added slowly and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture is passed throughThe pad was filtered, washed with EtOAc (500mL), and the filtrate was concentrated in vacuo. The residue was poured into saturated NaHCO₃Aqueous (380mL) and extracted with EtOAc (2X 500 mL). Separating the organic layer with Na-free₂SO₄Dried and concentrated in vacuo to afford 6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-amine X-16 and 2- (2, 2-difluoroethoxy) -6-methoxypyridin-3-amine X-17(0.32g of crude product, mixture of two regioisomers) as a brown solid.

¹H NMR (400MHz, DMSO-d6,1H NMR shows mixture of regioisomers) δ 3.99(s,3H)4.69-4.76(m,2H)6.64-6.68(m,1H)8.46(d, J ═ 3.91Hz,1H)8.48(d, J ═ 3.91Hz, 1H). (NH not visible)₂Protons).

A.17.Synthesis of 6-chloro-4-methoxy-pyridin-3-amine X-15:

step 1: synthesis of 4-methoxy-5-nitropyridin-2-ol X-18 a:

to a solution of 2-chloro-4-methoxy-5-nitro-pyridine (1.00g,5.30mmol) in H₂To a solution of O (25mL) was added KOH (1.49g, 26.5mmol) and the reaction mixture was heated at 60 ℃ for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature and poured into ice H₂In O (100mL), acidified to pH 4 with 1N HCl (8mL) at 0 ℃ and extracted with EtOAc (3X 70 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 4-methoxy-5-nitropyridin-2-ol X-18a (0.71g) as a pale yellow solid.

This compound was used in the next reaction without further purification.

Yield: 61 percent.

Basic LCMS method 2 (ES)⁺)：171(M+H)⁺And 77% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.83(s,3H)5.87(s,1H)8.48(s,1H)12.17(brs,1H)。

Step 2: synthesis of 2- (difluoromethoxy) -4-methoxy-5-nitropyridine X-18 b:

to CH with 4-methoxy-5-nitropyridin-2-ol X-18a (0.60g, 2.73mmol) at room temperature₃CN (20mL) and H₂To a solution of O (5mL) was added slowly KOH (0.77g, 13.6mmol) and diethylphosphonic acid bromodifluoromethyl ester (3.64g, 13.6mmol) and the reaction mixture was heated at 60 ℃ for 4 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture is washed with H₂O (60mL) was diluted and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (2X 50mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The reaction mixture was repeated 2.70g, the crude product from 2 reactions was beaten with a rod (club) and dissolved in DCM (150mL) and the resulting crude product was purified by column chromatography (silica, 100 mesh 200, 10% EtOAc in hexane) to give 2- (difluoromethoxy) -4-methoxy-5-nitropyridine X-18b (1.55g, 36%) as a light yellow liquid.

Yield: 36 percent.

Basic LCMS method 2 (ES)⁺)：221(M+H)⁺And 82% purity.

¹H NMR(400MHz,CDCl₃)δ4.05(s,3H)6.53(s,1H)7.52(t,J＝72Hz,1H)8.76(s,1H)。

And step 3: synthesis of 6- (difluoromethoxy) -4-methoxypyridin-3-amine X-18:

to a solution of 2- (difluoromethoxy) -4-methoxy-5-nitropyridine X-18b (1.50g, 5.62mmol) in MeOH (50mL) at room temperature was added 20% Pd/C (50% moisture, 0.18g), and the reaction mixture was stirred at room temperature under hydrogen pressure for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture is passed throughThe pad was filtered, washed with MeOH (2 × 60mL), and the filtrate was concentrated in vacuo. The resulting crude product was purified by column chromatography (silica, 100 mesh, 200 mesh, 30% EtOAc in hexane) to afford 6- (difluoromethoxy) -4-methoxypyridin-3-amine X-18(0.805g, 75%) as a white solid.

Yield: 36 percent.

Basic LCMS method 2 (ES)⁺)：191(M+H)⁺96% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.85(s,3H)4.72(s,2H)6.56(s,1H)7.44(s,1H)7.49(t,J＝74Hz,1H)。

A.18.6-cyclopropyl-2, 5-difluoropyridin-3-amine X-19 synthesis:

di-chloro-2, 5-difluoro-pyridin-3-amine X-2(0.25g, 1.52mmol) at room temperatureTo a solution of alkyl (8mL) was added cyclopropylboronic acid (0.27g, 3.18mmol) and Cs₂CO₃(1.24g,3.80mmol) of H₂O (2mL) solution, and the reaction mixture purged with argon for 10 min. Adding PdCl₂(dppf) (0.11g, 0.15mmol) and the reaction mixture was heated at 120 ℃ for 18 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to room temperature, filtered through a pad of celite, washed with EtOAc (2 × 60mL), and the filtrate was concentrated in vacuo. The residue is washed with H₂O (60mL) was diluted and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (70mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The resulting crude product was purified by column chromatography (silica, 100 mesh, 200 mesh, 8% EtOAc in hexane) to give 6-cyclopropyl-2, 5-difluoropyridin-3-amine X-19(0.10g) as a colorless liquid.

Yield: 37 percent.

Basic LCMS method 2 (ES)⁺)：171(M+H)⁺95% purity.

A.19.6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-amine X-20 synthesis:

to a solution of 6- (2, 2-difluoroethoxy) -2, 5-difluoropyridin-3-amine X-13(1.00g,4.76mmol) in THF (15mL) at 0 deg.C was added NaOMe (25% in MeOH, 1.13g, 5.23mmol) slowly and the reaction mixture was heated at 80 deg.C for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was taken up in ice-cold H₂O (50mL) was quenched and extracted with EtOAc (2X 100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The resulting crude product was purified by column chromatography (silica, 100 mesh, 200 mesh, 5 to 10% EtOAc in hexane) to give 6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-amine X-20(0.55g) as a brown liquid.

Yield: 50 percent.

Basic LCMS method 2 (ES)⁺)：223(M+H)⁺91% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.85(s,3H)4.50(td,J＝14.89,3.69Hz,2H)4.74(s,2H)6.23-6.54(m,1H)6.96(d,J＝11.32Hz,1H)。

A.20.synthesis of 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-amine X-21:

step 1: synthesis of 2- (2- (difluoromethoxy) ethoxy) -3-fluoro-6-methoxy-5-nitropyridine X-21 a:

to a solution of 3-fluoro-6-methoxy-5-nitro-pyridin-2-ol X-8a (0.10g,0.53mmol) in DMF (4mL) at room temperature was added K₂CO₃(0.22g,1.59mmol) and 1-bromo-2- (difluoromethoxy) ethane (0.09g, 0.53mmol),and the reaction mixture was heated in a microwave at 90 ℃ for 2 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled at room temperature and poured into H₂O (50mL) and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (2X 50mL), and dried over anhydrous Na₂SO₄Dried and concentrated in vacuo to give 2- (2- (difluoromethoxy) ethoxy) -3-fluoro-6-methoxy-5-nitropyridine X-21a (0.09g) as a brown liquid.

This compound was used in the next reaction without further purification.

Yield: and 64 percent.

¹H NMR(400MHz,DMSO-d₆)δ4.05(s,3H)4.22-4.27(m,2H)4.70-4.76(m,2H)6.75(t,J＝74Hz,1H)8.57(d,J＝9.78Hz,1H)。

Step 2: synthesis of 6- (2- (difluoromethoxy) ethoxy) -5-fluoro-2-methoxypyridin-3-amine X-21:

to CH with 2- (2- (difluoromethoxy) ethoxy) -3-fluoro-6-methoxy-5-nitropyridine X-21a (0.09g, 0.32mmol) at 0 deg.C₃To the COOH (2mL) solution was added slowly iron (0.18g, 3.19mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of celite, washed with EtOAc (50mL), and the filtrate was concentrated in vacuo. The residue was poured into saturated NaHCO₃Aqueous (10mL) and extracted with EtOAc (2X 50 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by washing with pentane (3 × 70mL) to obtain 6- (2- (difluoromethoxy) ethoxy) -5-fluoro-2-methoxypyridin-3-amine X-21(0.08g, 77%) as a brown solid.

This compound was used in the next reaction without further purification.

MS(ESI)m/e[M+H]+/Rt/％：253.00/1.72/77.7％

Yield: 77 percent.

Basic LCMS method 2 (ES)⁺)：253(M+H)⁺78% purity.

A.21.Synthesis of 6-chloro-4-methoxy-pyridin-3-amine X-22:

to a solution of 6-chloro-5-fluoro-2-methoxy-pyridin-3-amine X-3(2.0g, 11.33mmol) in MeOH (38mL) under argon atmosphere for 5 minutes was added Pd/C (20%, 0.43g) and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through a pad of celite and washed with EtOAc (3 × 100 mL). The filtrate was concentrated in vacuo. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 4 to 10% EtOAc in hexane) to afford 5-fluoro-2-methoxy-pyridin-3-amine X-22(0.48g) as a brown solid.

Yield: 30 percent.

Basic LCMS method 2 (ES)⁺)：143(M+H)⁺96% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.83(s,3H)5.32(br s,2H)6.72(dd,J＝2.8,9.6Hz,1H)7.24(d,J＝2.8Hz,1H)。

A.22.Synthesis of 6-cyclopropyl-5-fluoro-2-methoxypyridin-3-amine X-23:

to a solution of 6-cyclopropyl-2, 5-difluoropyridin-3-amine X-19(1.50g, 8.75mmol) in MeOH (20mL) at room temperature was added NaOMe (25% in MeOH, 3.78mL, 17.5mmol) and the reaction mixture was heated at 100 deg.C for 24 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue is washed with H₂O (20mL) was diluted and extracted with EtOAc (3X 25 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by combined flash chromatography (20% EtOAc in hexanes) to afford 6-cyclopropyl-5-fluoro-2-methoxypyridin-3-amine X-23(1.10g) as a brown oil。

Yield: and 69 percent.

Basic LCMS method 2 (ES)⁺)：183(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ0.76-0.86(m,4H)1.94-2.03(m,1H)3.75(s,3H)4.94(s,2H)6.68(d,J＝10.76Hz,1H)。

B. Synthesis of intermediates of formula XI

B.1.Synthesis of 6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine XI-1:

at 0 ℃ in the presence of 1H-pyrrolo [2,3-b]To a solution of pyridine-6-carbaldehyde (196mg,1.26mmol) in dichloromethane (4mL) was added diethylaminosulfur trifluoride (260. mu.L, 1.91 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction was poured into ice and NaHCO₃The mixture was extracted 3 times with DCM. With Na₂SO₄Drying the organic phase and concentrating the solvent to obtain 6- (difluoromethyl) -1H-pyrrolo [2,3-b]Pyridine XI-1(96mg) as a brown solid.

Yield: 45 percent.

Basic LCMS method 1 (ES)⁺)：169(M+H)⁺And 82% purity.

B.2.Synthesis of 6- (difluoromethoxy) -1H-indole XI-2:

step 1: synthesis of tert-butyl 6- ((tert-butoxycarbonyl) oxy) -1H-indole-1-carboxylate XI-2 a:

to CH with 1H-indol-6-ol (5.00g,37.6mmol)₃To a solution of CN (50mL) were added di-tert-butyl dicarbonate (25.9mL, 113mL), DMAP (2.29g, 18.8mmol) and triethylamine (15.7mmol, 113 mmol). The reaction mixture was stirred at 25 ℃ for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. Will obtainThe crude product of (2) was purified by column chromatography (silica, 100-mesh 200-mesh, 20% EtOAc in hexane) to obtain tert-butyl 6- ((tert-butoxycarbonyl) oxy) -1H-indole-1-carboxylate XI-2a (10.0g) as a pale yellow liquid.

Yield: 80 percent.

Basic LCMS method 2 (ES)^-)：332(M-H)^-And 99% purity.

Step 2: synthesis of 6-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester XI-2 b:

to a solution of tert-butyl 6- ((tert-butoxycarbonyl) oxy) -1H-indole-1-carboxylate XI-2a (9.90g,29.6mmol) in DCM (100mL) was added morpholine (51.8mL, 592mmol) and the reaction mixture was stirred at room temperature for 16H. The progress of the reaction was monitored by TLC. After completion, the reaction mixture is washed with H₂Diluted O (200mL) and extracted with EtOAc (3X 100 mL). The organic layer was separated, washed with brine (2X 100mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100-mesh 200, 15% EtOAc in hexane) to give tert-butyl 6-hydroxy-1H-indole-1-carboxylate XI-2b (6.70g) as a colorless oil.

Yield: 97 percent.

¹H NMR(400MHz,DMSO-d₆)δ1.61(s,9H)6.55(d,J＝3.94Hz,1H)6.71(dd,J＝8.37,1.97Hz,1H)7.36(d,J＝8.86Hz,1H)7.43(d,J＝3.45Hz,1H)7.51(s,1H)9.41(s,1H)。

And step 3: synthesis of 6- (difluoromethoxy) -1H-indole-1-carboxylic acid tert-butyl ester XI-2 c:

to CH with 6-hydroxy-1H-indole-1-carboxylic acid tert-butyl ester XI-2b (2.00g, 8.57mmol) at-78 deg.C₃CN (20mL) and H₂To a solution of O (20mL) was added KOH (9.62g,171mmol) and diethylphosphonic acid bromodifluoromethyl ester (3.05mL, 17.1mmol) slowly. After 15 minutes, the reaction mixture was stirred at 0 ℃ for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture is washed with H₂O (200mL) was diluted and extracted with EtOAc (2X 200 mL). The organic layer was separated, washed with brine (2X 30mL), and dried over anhydrous Na₂SO₄Dried and under vacuumAnd (5) concentrating. The crude product obtained was purified by column chromatography (silica, 100-200 mesh, 15% EtOAc in hexane) to give tert-butyl 6- (difluoromethoxy) -1H-indole-1-carboxylate XI-2c (0.68g) as a yellow oil.

Yield: 21 percent.

Basic LCMS method 2 (ES)^-)282(M-H)^-And 74% purity.

¹H NMR(400MHz,DMSO-d₆)δ1.63(s,9H)6.73(d,J＝3.91Hz,1H)7.09(dd,J＝8.80,1.47Hz,1H)7.23(t,J＝76Hz,1H)7.66(d,J＝8.31Hz,1H)7.69(d,J＝3.42Hz,1H)7.86(s,1H)。

And 4, step 4: synthesis of 6- (difluoromethoxy) -1H-indole XI-2:

to a solution of 6- (difluoromethoxy) -1H-indole-1-carboxylic acid tert-butyl ester XI-2c (0.67g, 1.76mmol) in DCM (25mL) at 0 deg.C was added TFA (40mL), and the reaction mixture was stirred at the same temperature for 5 min, then at room temperature for 1H. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum. The residue is washed with H₂O (100mL), saturated NaHCO₃Diluted (50mL) and extracted with EtOAc (2X 200 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated in vacuo to give 6- (difluoromethoxy) -1H-indole XI-2(0.31g) as a brown oil.

Yield: 76 percent.

Basic LCMS method 2 (ES)^-)：182(M-H)^-And 79% purity.

¹H NMR(400MHz,DMSO-d₆)δ6.42-6.44(m,1H)6.83(dd,J＝8.56,1.71Hz,1H)7.14(t,J＝74Hz,1H)7.18(s,1H)7.37(t,J＝2.45Hz,1H)7.54(d,J＝8.80Hz,1H)11.17(brs,1H)。

B.3.Synthesis of 6-chloro-7-fluoro-1H-indole XI-3:

to a solution of 1-chloro-2-fluoro-3-nitro-benzene (2.50g, 14.2mmol) in THF (50mL) at-78 deg.C was addedVinylmagnesium bromide (5.61g, 42.7mmol) and the mixture was stirred at the same temperature for 1 hour. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was taken up with saturated NH₄Cl (100mL) quench with H₂O (400mL) was diluted and extracted with EtOAc (500 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100-mesh 200 mesh, 5% EtOAc in hexane) to give 6-chloro-7-fluoro-1H-indole XI-3(0.60g) as a red liquid.

Yield: 17 percent.

Basic LCMS method 2 (ES)^-)：168.00(M-H)^-And 66% purity.

B.4.Synthesis of 1- (benzenesulfonyl) -6-benzyloxypyrrolo [2,3-b ] pyridine XI-4:

step 1: synthesis of 1- (phenylsulfonyl) -6-methoxypyrrolo [2,3-b ] pyridine XI-4a

6-methoxy-1H-pyrrolo [2,3-b ] is treated with sodium hydride (60% in paraffin, 238mg, 6mmol) at room temperature]A solution of pyridine (998mg, 5.4mmol) in 10mL of DMF was stirred for 1 hour. Benzenesulfonic acid chloride (0.8mL, 6.5mmol) was then added. The reaction mixture was stirred at room temperature for 18 h, water (100mL) was added and the suspension was extracted with ethyl acetate (3X 30 mL). The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography and purified with (petroleum ether: ethyl acetate 80: 20). The collected fractions were evaporated to yield 980mg of 1- (phenylsulfonyl) -6-methoxy-pyrrolo [2,3-b ]]Pyridine XI-4a, as a white powder.

Yield: and 63 percent.

Neutral LCMS method 3 (ES)⁺)：289(M+H)⁺100% purity.

¹H NMR(600MHz,DMSO-d₆)δ3.89(s,3H)，6.71(dd,J＝6.2,2.3Hz,2H)，7.67-7.61(m,3H)，7.75-7.70(m,1H)，7.91(d,J＝8.5Hz,1H)，8.13(dd,J＝8.5,1.3Hz,2H)。

Step 2: synthesis of 1- (phenylsulfonyl) pyrrolo [2,3-b ] pyridin-6-ol XI-4b

To the solution of 1- (benzenesulfonyl) -6-methoxy-pyrrolo [2,3-b ] at 0 DEG C]Pyridine XI-4a (800mg, 2.7mmol) in dichloromethane (35mL) was added to a solution of boron tribromide at 1.0M in dichloromethane (5mL,5mmol), then warmed to room temperature and stirred at the same temperature for 95 h. By adding saturated NaHCO₃The solution (40mL) hydrolyzed the reaction mixture. Water was added and the aqueous phase was extracted with ethyl acetate (3X 35 mL). The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (petroleum ether: ethyl acetate 80: 20). The collected fractions were evaporated to yield 580mg of 1- (phenylsulfonyl) pyrrolo [2,3-b ]]Pyridin-6-ol XI-4b as a white powder.

Yield: 79 percent.

Neutral LCMS method 3 (ES)⁺)：275(M+H)⁺And 93% purity.

¹H NMR(600MHz,DMSO-d₆)δ6.58(d,J＝8.4Hz,1H)，6.66(d,J＝4.0Hz,1H)，7.55(d,J＝4.0Hz,1H)，7.64-7.58(m,2H)，7.75-7.69(m,1H)，7.84(d,J＝8.4Hz,1H)，8.20-8.14(m,2H)，10.92(s,1H)。

And step 3: synthesis of 1- (phenylsulfonyl) -6-benzyloxypyrrolo [2,3-b ] pyridine XI-4

A mixture of 1- (phenylsulfonyl) pyrrolo [2,3-b ] pyridin-6-ol XI-4b (767mg, 2.8mmol), benzyl bromide (0.29mL, 205mmol, 0.89 equiv.), and potassium carbonate (967.2mg, 7mmol, 2.5 equiv.) in dry acetonitrile (20mL) was heated at 50 ℃ for 22 hours under argon. After cooling, the reaction mixture was filtered to remove unreacted potassium carbonate and washed thoroughly with ethyl acetate (100 mL). After evaporation of the organic solvent, 1- (benzenesulfonyl) -6-benzyloxy-pyrrolo [2,3-b ] pyridine XI-4 was obtained as a white solid (600 mg).

This compound was used in the next reaction without further purification.

Yield: 59 percent.

Neutral LCMS method 3 (ES)⁺)：365(M+H)⁺Crude product

C. Synthesis of intermediates of formula XII

C.1.6-chloro-1H-indole-3-sulfonyl chloride XII-1 Synthesis

Step 1: synthesis of 6-chloro-1H-indole-3-sulfonic acid XII-1 a:

to a solution of 6-chloroindole (1.00g, 6.62mmol) in pyridine (10mL) was added sulfur trioxide pyridine trioxide complex (1.57g, 9.93mmol) and the reaction mixture was heated to reflux for 16 h. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture is washed with H₂Diluted O (100mL) and Et₂O (250 mL). The aqueous layer was separated and concentrated under vacuum. The resulting crude product was co-evaporated with toluene to give 6-chloro-1H-indole-3-sulfonic acid XII-1a (2.30g crude product) as a brown semisolid.

This compound was used in the next reaction without further purification.

Basic LCMS method 2 (ES)^-)：230(M-H)^-And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ6.98-7.04(m,1H)，7.12-7.26(m,1H)，7.44(s,1H)，7.69-7.75(m,1H)，11.13(brs,1H)。

Step 2: synthesis of 6-chloro-1H-indole-3-sulfonyl chloride XII-1:

to a solution of sulfolane (5mL) and CH in 6-chloro-1H-indole-3-sulfonic acid XII-1a (2.00g,6.45mmol) at 0 deg.C₃POCl was added dropwise to CN (5mL) solution₃(1.30mL,14.2mmol) and the reaction mixture was heated at 70 ℃ for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was taken up in ice-cold H₂O (100mL) was quenched and extracted with EtOAc (2X 50 mL). The organic layer was separated, washed with brine (50mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica,100 mesh, 30% EtOAc in hexane) to obtain 6-chloro-1H-indole-3-sulfonyl chloride XII-1(1.00g) as a pale pink solid.

Yield: 62 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.32(dd,J＝8.56,1.22Hz,1H)，7.71(s,1H)，8.03(d,J＝8.80Hz,1H)，8.45(d,J＝2.93Hz,1H)，12.38(brs,1H)。

C.2.Synthesis of 6-bromo-1H-indole-3-sulfonyl chloride XII-2:

to CH with 6-bromo-1H-indole (5g, 25.5mmol) at 0 deg.C₃Adding ClSO into CN (60mL) solution₃H (1mL), and the reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into ice-cold H₂O (200mL) and stirred for 30 min. A solid precipitated, which was filtered and dried under vacuum to give 6-bromo-1H-indole-3-sulfonyl chloride XII-2(5g) as a brown solid.

This compound was used in the next reaction without further purification.

Yield: 66 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.38-7.48(m,1H)7.85(s,1H)7.97(d,J＝8.37Hz,1H)8.44(d,J＝3.45Hz,1H)12.55(brs,1H)。

C.3.synthesis of 1- (benzenesulfonyl) -6-chloro-indole-3-sulfonyl chloride XII-3:

step 1: synthesis of 1- (phenylsulfonyl) -6-chloro-indole XII-3a

A suspension of finely powdered sodium hydroxide (24.5g,613mmol) in dichloromethane (300mL) was stirred in an ice bath and 6-chloroindole (30g, 197mmol) was added in one portion followed by tetrabutylammonium hydrogen sulfate (1.75g, 5.15 mmol). Benzenesulfonyl chloride (2.2mL, 218mmol) was then added dropwise over 20 minutes and the reaction mixture was stirred at 0 ℃ for 1 hour. The ice bath was then removed and the mixture was stirred at room temperature for an additional 1 hour. When LC/MS showed the reaction was complete, the reaction mixture was filtered through a pad of celite, which was washed with DCM and the combined filtrate and washings were evaporated to dryness. The product was triturated in ether, filtered, washed with a small amount of ether then hexanes and dried, the filtrate was concentrated to give a second crop of product, 50.54g total of 1- (benzenesulfonyl) -6-chloro-indole XII-3a as a light brown solid.

Yield: 88 percent.

¹H NMR(400MHz,CDCl₃)δ8.04(dd,J＝1.8,0.9Hz,1H)，7.91(t,J＝1.4Hz,1H)，7.89(t,J＝1.8Hz,1H)，7.67-7.54(m,2H)，7.53-7.48(m,2H)，7.48-7.42(m,1H)，7.23(dd,J＝8.4,1.9Hz,1H)，6.65(dd,J＝3.7,0.9Hz,1H)。

Step 2: synthesis of 1- (phenylsulfonyl) -6-chloro-indole-3-sulfonyl chloride XII-3

A solution of 1- (phenylsulfonyl) -6-chloro-indole XII-3a (50g, 171.4mmol) in acetonitrile (500mL) was stirred in an ice bath, chlorosulfonic acid (100.8g, 856.8mmol) was added dropwise over 20 minutes, and the reaction mixture was stirred at room temperature for 5 days. It was then poured slowly into ice water (2.2L) with stirring for 20 minutes, filtered, washed several times with water and dried under suction to give 63.77g of 1- (benzenesulfonyl) -6-chloro-indole-3-sulfonyl chloride XII-3 as a light brown solid.

Yield: 95 percent.

¹H NMR(400MHz,CDCl₃)δ8.36(s,1H)，8.07(d,J＝1.8Hz,1H)，8.04(t,J＝1.3Hz,1H)，8.02(d,J＝1.5Hz,1H)，7.91(d,J＝8.6Hz,1H)，7.79-7.70(m,1H)，7.68-7.59(m,2H)，7.47(dd,J＝8.6,1.8Hz,1H)。

C.4.Synthesis of 1- (benzenesulfonyl) -6-chloro-pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-4:

step 1: synthesis of 1- (phenylsulfonyl) -6-chloro-pyrrolo [2,3-b ] pyridine XII-4a

To a solution of 6-chloro-1H-pyrrolo [2,3-b ] pyridine (1.37g, 8.97mmol) in DMF (100mL) was added sodium hydride (60% in paraffin, 1g, 41 mmol). The solution was stirred for 30 minutes, allowed to warm from 0 ℃ to room temperature. Next, benzenesulfonyl chloride (1.5mL, 11.8mmol) was added dropwise. The suspension was stirred at room temperature for 3 hours and hydrolyzed with ice water. The resulting solid was filtered off under reduced pressure, washed thoroughly with water (75mL) and finally with petroleum ether (15 mL). The resulting material was dried at 60 ℃ and purified by column chromatography (eluent: pure dichloromethane) to give 856mg of 1- (benzenesulfonyl) -6-chloro-pyrrolo [2,3-b ] pyridine XII-4a as a brown solid.

Yield: 32 percent.

Step 2: synthesis of 1- (phenylsulfonyl) -6-chloro-pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-4

The obtained 1- (benzenesulfonyl) -6-chloro-pyrrolo [2,3-b ] is used]Pyridine XII-4a (150mg, 0.51mmol) was dissolved in acetonitrile (5mL) and treated dropwise with chlorosulfonic acid (2mL, 2.91 mmol). The mixture was refluxed for 3 hours, cooled to room temperature, hydrolyzed with ice water (50mL) and neutralized with saturated sodium bicarbonate solution. The crude product was extracted with dichloromethane (3 times 50mL each). The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated. The resulting material was purified by column chromatography (eluent: pure dichloromethane) to give 163mg of 1- (benzenesulfonyl) -6-chloro-pyrrolo [2,3-b ] -a]Pyridine-3-sulfonyl chloride XII-4 as a light yellow solid.

Yield: 81 percent.

¹H NMR(600MHz,CDCl₃)δ:8.48(s,1H),8.32(d,J＝7.8Hz,2H)，8.18(d,J＝8.3Hz,1H)，7.71(t,J＝7.5Hz,1H)，7.60(t,J＝7.9Hz,2H)，7.41(d,J＝8.4Hz,1H)。

C.5.Synthesis of 1- (benzenesulfonyl) -6- (difluoromethyl) pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-5

Step 1: synthesis of 1- (phenylsulfonyl) -6- (difluoromethyl) pyrrolo [2,3-b ] pyridine XII-5a

A suspension of sodium hydroxide (76mg, 1.88mmol) in dichloromethane (1mL) was stirred in an ice bath and 6- (difluoromethyl) -1H-pyrrolo [2,3-b ] was added]Pyridine XI-14(125mg, 0.74mmol) was added followed by tetrabutylammonium hydrogen sulfate (7.5g, 0.022 mmol). Then, benzenesulfonyl chloride (105 μ L, 0.81mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered through a pad of celite, which was washed with DCM and the combined filtrate and washings were evaporated to dryness. By chromatography (SiO)₂Eluting with dichloromethane) to obtain 1- (benzenesulfonyl) -6- (difluoromethyl) pyrrolo [2,3-b ]]Pyridine XII-5a (200mg) as a light brown solid.

Yield: 70 percent.

Basic LCMS method 1 (ES)⁺)：309(M+H)⁺100% purity.

Step 2: synthesis of 1- (phenylsulfonyl) -6- (difluoromethyl) pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-5

A solution of 1- (benzenesulfonyl) -6- (difluoromethyl) pyrrolo [2,3-b ] pyridine XII-5a (76mg,0.24mmol) in acetonitrile (10mL) was stirred in an ice bath and chlorosulfonic acid (54 μ L, 0.78mmol) was added dropwise and the reaction mixture was stirred at 50 ℃ for 4 days. Then, phosphorus oxychloride (100. mu.L, 1.06mmol) was added and the reaction mixture was heated at 70 ℃ overnight. After cooling, it was then poured slowly into ice water and extracted with chloroform (3 ×). The organic layer was dried over magnesium sulfate and evaporated to dryness to give 1- (benzenesulfonyl) -6-chloro-indole-3-sulfonyl chloride XII-5(100mg) as a solid.

This compound was used in the next reaction without further purification.

Yield: 95 percent.

Base LCMS method 1 (ES)^-)：387(M-H)^-(corresponding sulfonic acid mass), 88% purity.

C.6.Synthesis of 1- (phenylsulfonyl) -6- (difluoromethyl) indole-3-sulfonyl chloride XII-6

Step 1: synthesis of 1- (phenylsulfonyl) indole-6-carbaldehyde XII-6a

To a stirred suspension in dichloromethane (130mL) with finely powdered sodium hydroxide (8.26g, 206.7mmol) previously cooled on an ice bath was added 1H-indole-6-carbaldehyde (10.0g,68.89mmol) as a single portion followed by tetrabutylammonium hydrogen sulfate (1.754g, 5.17 mmol). Stirring was continued for an additional 10 minutes, then a solution of benzenesulfonyl chloride (9.67mL, 75.78mmol, 1.1 equiv.) in dichloromethane (20mL) was added dropwise over 20 minutes and the reaction mixture was stirred at 0 ℃ for 1 hour. The cooling bath was removed and the mixture was stirred at ambient temperature for an additional 1 hour. The reaction mixture was filtered through a Kieselguhr pad, the filter cake was rinsed with dichloromethane (2 x 100mL), and the filtrate was concentrated in vacuo. The residue was then triturated in ether (100mL), the solid collected by filtration, and the filter cake rinsed with ether (2X 50 mL). The solid was then dried under vacuum to obtain 17.5g of the title compound (contaminated with tetrabutylammonium hydrogen sulfate,. about.8% w/w). The solid was dissolved in ethyl acetate (350mL), the solution was washed with water (150mL) and brine (100mL), dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under vacuum to give 1- (benzenesulfonyl) indole-6-carbaldehyde XII-6a (15.29g) as a dark beige solid.

Yield: 70 percent.

Acidic LCMS method 4 (ES)⁺)：286(M+H)⁺And 84% purity.

¹H NMR(400MHz,CDCl₃)δ6.74(dd,J＝3.6,0.7Hz,1H)，7.52-7.44(m,2H)，7.60-7.53(m,1H)，7.66(d,J＝8.2Hz,1H)，7.81-7.75(m,2H)，7.98-7.88(m,2H)，8.54-8.45(m,1H)，10.09(s,1H)。

Step 2: synthesis of 1- (phenylsulfonyl) -6- (difluoromethyl) indole XII-6b

To a stirred solution of 1- (phenylsulfonyl) indole-6-carbaldehyde XII-6a (3.58g,12.55mmol) in dichloromethane (55mL) was added dropwise diethylaminosulfur fluoride (7.5mL, 56.77 mmol). Stirring was continued at ambient temperature for 21 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (100mL) and then extracted with dichloromethane (2X 150 mL). The combined organic layers were washed with brine (100mL), dried over anhydrous sodium sulfate, filtered and the solvent was concentrated in vacuo. The residue was purified using flash chromatography (340g KP-SIL column) with an ethyl acetate gradient in heptane (5% -30%) to give 1- (benzenesulfonyl) -6- (difluoromethyl) indole XII-6b (2.91g) as an off-white solid.

Yield: 75 percent.

Acidic LCMS method 4 (ES)⁺)：308(M+H)⁺100% purity.

¹H NMR(400MHz,CDCl₃)δ6.70(dd,J＝3.7,0.7Hz,1H)，6.76(t,J＝56.5Hz,1H)，7.39(dd,J＝8.2,0.8Hz,1H)，7.50-7.42(m,2H)，7.59-7.51(m,1H)，7.64-7.59(m,1H)，7.66(d,J＝3.7Hz,1H)，7.93-7.85(m,2H)，8.17(d,J＝0.8Hz,1H)。

And step 3: synthesis of 1- (phenylsulfonyl) -6- (difluoromethyl) indole-3-sulfonyl chloride XII-6

To a stirred solution of 1- (benzenesulfonyl) -6- (difluoromethyl) indole XII-6b (5.7g, 18.55mmol) in acetonitrile (57mL), cooled on ice in advance, chlorosulfonic acid (10.8g, 92.74mmol) was added dropwise over 20 minutes, and the reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was poured slowly into ice water (220mL) with stirring over 20 minutes. The precipitated solid was collected by filtration and the filter cake was rinsed with ice water (3X 25 mL). The filter cake was then dried under a stream of nitrogen for 1 hour, rinsed with cyclohexane (25mL) and dried under a stream of nitrogen for an additional 2 hours to give 1- (benzenesulfonyl) -6- (difluoromethyl) indole-3-sulfonyl chloride XII-6(7.51g) as an off-white solid.

Yield: 99 percent.

¹H NMR(400MHz,DMSO-d₆)δ7.20(t,J＝55.9Hz,1H)，7.51(d,J＝8.3Hz,1H)，7.75-7.57(m,3H)，7.76(s,1H)，7.91(d,J＝8.2Hz,1H)，8.11-8.01(m,2H)，8.14(s,1H)。

C.7.Synthesis of 6-chloro-1H-pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-7:

reacting 6-chloro-1H-pyrrolo [2,3-b ]]Pyridine (0.50g, 3.28mmol) in ClSO₃The mixture in H (10mL) was heated at 90 ℃ for 16H. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was washed with ice H₂O (30mL), filtered, quenched with H₂O (30mL) was washed and dried under vacuum to give 6-chloro-1H-pyrrolo [2,3-b ]]Pyridine-3-sulfonyl chloride XII-7(0.45g) as an off-white solid.

This compound was used in the next reaction without further purification.

Yield: and 55 percent.

Basic LCMS method 2 (ES)^-)：230(M-H)^-(corresponding sulfonic acid), 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ7.16(d,J＝7.98Hz,1H)7.50(d,J＝2.99Hz,1H)8.08(d,J＝8.48Hz,1H)11.88(brs,1H)

C.8.Synthesis of 6- (difluoromethoxy) -1H-indole-3-sulfonyl chloride XII-8:

step 1: synthesis of 6- (difluoromethoxy) -1H-indole-3-sulfonic acid XII-8 a:

to CH of 6- (difluoromethoxy) -1H-indole XI-2(0.30g, 1.30mmol) at 0 deg.C₃CN (15mL) solution was added slowly to ClSO₃H (0.13mL, 1.95mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice-cold H₂O (50mL) and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (20mL) and concentrated in vacuo to afford 6- (difluoromethoxy) -1H-indole-3-sulfonic acid XII-8a (0.33g crude product) as a brown semisolid.

Basic LCMS method 2 (ES)^-)：262(M-H)^-And 75% purity.

Step 2: synthesis of 6- (fluoromethoxy) -1H-indole-3-sulfonyl chloride XII-8:

to a solution of 6- (difluoromethoxy) -1H-indole-3-sulfonic acid XII-8a (0.15g,0.43mmol) in DCM (5mL) was added oxalyl chloride (0.15mL,1.70mmol) followed by DMF (0.007mL, 0.09mmol) at 0 deg.C and the reaction mixture was stirred at room temperature for 3H. The reaction progress was monitored via TLC and LCMS. After completion, the reaction mixture was concentrated in vacuo to obtain 6- (difluoromethoxy) -1H-indole-3-sulfonyl chloride XII-8(0.13g crude product) as a brown semisolid.

This compound was used in the next reaction without further purification.

Basic LCMS method 2 (ES)^-)：262(M-H)^-(corresponding sulfonic acid), 80% purity.

C.9.Synthesis of 6-chloro-7-fluoro-indole-3-sulfonyl chloride XII-9- (phenylsulfonyl) -1

Step 1: synthesis of 1- (phenylsulfonyl) -6-chloro-7-fluoro-indole XII-9a

To a stirred suspension of fine powdered sodium hydroxide (3.54g,0.088mol) in dichloromethane (60mL) with prior cooling on an ice bath was added 6-chloro-7-fluoro-1H-indole XI-3(5g, 0.029mol) in one portion followed by tetrabutylammonium hydrogen sulfate (0.501g, 0.001 mol). Stirring was continued for 10 min, then a solution of benzenesulfonyl chloride (4.2mL, 0.033mol) in dichloromethane (15mL) was added dropwise over 20 min, and the reaction mixture was stirred at 0 ℃ for 1 h. The ice bath was removed and the mixture was stirred at ambient temperature for an additional 1 hour. The reaction mixture was filtered through a Kieselguhr pad and the filter cake was rinsed with dichloromethane (2X 50 mL). The filtrate was washed with water (4 × 50mL) and brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 1- (benzenesulfonyl) -6-chloro-7-fluoro-indole XII-9a (8.57g) as a dark beige solid.

Yield: 90 percent.

¹H NMR(400MHz,DMSO-d₆)δ6.95(dd,J＝3.7,2.3Hz,1H)，7.37(dd,J＝8.4,6.2Hz,1H)，7.48(d,J＝8.6Hz,1H)，7.66(tt,J＝6.9,1.9Hz,2H)，7.80-7.71(m,1H)，7.98-7.91(m,2H)，7.99(d,J＝3.7Hz,1H)。

Step 2: synthesis of 1- (phenylsulfonyl) -6-chloro-7-fluoro-indole-3-sulfonyl chloride XII-9

To a stirred solution of 1- (benzenesulfonyl) -6-chloro-7-fluoro-indole XII-9a (8.50g,0.027mol) in acetonitrile (85mL), cooled previously on an ice batch, chlorosulfonic acid (9.12mL, 0.137mol) was added dropwise over 20 minutes and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured slowly into ice water (340mL) with stirring over 20 minutes. The precipitated solid was collected by filtration and the filter cake was rinsed with ice water (3X 50mL) and cyclohexane (50 mL). The filter cake was then dried under a stream of nitrogen for 2 hours and then in a vacuum oven at 40 ℃ for 16 hours to give 1- (benzenesulfonyl) -6-chloro-7-fluoro-indole-3-sulfonyl chloride XII-9(7.82g) as a pale pink solid.

Yield: 66 percent.

Acidic LCMS method 4 (ES)⁺)：388(M+H)⁺95% purity.

¹H NMR(400MHz,DMSO-d₆)δ7.44(dd,J＝8.5,6.3Hz,1H)，7.72-7.61(m,3H)，7.80-7.72(m,1H)，7.81(s,1H)，8.05-7.98(m,2H)。

C.10.Synthesis of 1- (phenylsulfonyl) -6-methyl-indole-3-sulfonyl chloride XII-10

Step 1: synthesis of 1- (phenylsulfonyl) -6-methyl-indole XII-10a

To a solution of 6-methyl-1H-indole (1g,7.39mmol) in THF (20mL) at 0 deg.C was added sodium hydride (60% in paraffin, 0.35g, 8.9 mmol). The solution was stirred for 30 minutes, allowed to warm from 0 ℃ to room temperature. Next, benzenesulfonyl chloride (1.1mL, 8.9mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and hydrolyzed with water. And then extracted with EtOAc. The organic layer was separated, washed with brine, and MgSO₄Dried and concentrated under vacuum. The residue was purified by column chromatography (eluent: 25-40% AcOEt in heptane) to yield 1.97g of1- (benzenesulfonyl) -6-methyl-indole XII-10a as a colorless oil.

Yield: 70 percent.

Basic LCMS method 1 (ES)^-)：270(M-H)^-71% purity.

Step 2: synthesis of 1- (phenylsulfonyl) -6-methyl-indole-3-sulfonyl chloride XII-10

The resulting 1- (benzenesulfonyl) -6-methyl-indole XII-10a (0.9g, 3.15mmol) was diluted in acetonitrile (9mL) and treated dropwise with chlorosulfonic acid (0.32mL, 4.72 mmol). After 2 hours, phosphorus oxychloride (0.65mL, 6.93mmol) was added and the reaction mixture was heated at 70 ℃ overnight. After cooling to room temperature and dilution with chloroform, the organic layer was separated and washed with water and then brine. The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated in vacuo to afford 1.4g of 1- (benzenesulfonyl) -6-methyl-indole-3-sulfonyl chloride XII-10 as a brown solid.

This compound was used in the next reaction without further purification.

Basic LCMS method 1 (ES)^-)：419(M-H)^-Aliquots were quenched with morpholine (aliquot) prior to analysis

C.11.Synthesis of 1- (phenylsulfonyl) -6-methoxy-indole-3-sulfonyl chloride XII-11

Step 1: synthesis of 1- (phenylsulfonyl) -6-methoxy-indole XII-11a

To a solution of 6-methoxyindole (2.5g, 17mmol) in DMF (50mL) at 0 deg.C was added sodium hydride (60% in paraffin, 1.7g, 71 mmol). The suspension was stirred for 30 minutes and then warmed to room temperature. Subsequently, benzenesulfonyl chloride (2.8mL, 3.70g, 22mmol) was added dropwise with stirring to treat the solution. After stirring at room temperature for 2.5 hours, ice water was added to the reaction mixture under vigorous stirring. The resulting precipitate was filtered off under reduced pressure, washed thoroughly with water (100mL), followed by petroleum ether (10 mL). After drying at 60 ℃ 1- (phenylsulfonyl) -6-methoxy-indole XII-11a was obtained as a colorless solid (3.2 g).

Yield: 65 percent.

1H NMR(600MHz,CDCl3)δ:7.87-7.81(m,2H)，7.53-7.48(m,2H)，7.45-7.39(m,3H)，7.36(d,J＝8.5Hz,1H)，6.84(dd,J＝8.6/2.3Hz,1H)，6.56(dd,J＝3.7/0.9Hz,1H)，3.85(s,3H)。

Step 2: synthesis of 1- (phenylsulfonyl) -6-methoxy-indole-3-sulfonyl chloride XII-11

A solution of 1- (phenylsulfonyl) -6-methoxyindole XII-11a (500mg, 1.74mmol) in dichloromethane (15mL) was treated with SO₃DMF complex (1.2g, 7.8mmol) was treated and stirred at room temperature for 2h (TLC control). The expected intermediate indolesulfonic acid is not isolated. Next, thionyl chloride (thionyl chloride) (1mL, 14mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was washed with saturated NaHCO₃The solution (50mL) was hydrolyzed and extracted with dichloromethane (3 times 50mL each). The combined organic extracts were extracted with MgSO₄Dried, filtered and concentrated by evaporation in vacuo. The residue was purified by column chromatography (silica gel 60, eluent, dichloromethane/petroleum ether ═ 1: 1) to give 1- (benzenesulfonyl) -6-methoxy-indole-3-sulfonyl chloride XII-11 as a colorless solid (504 mg).

Yield: 75 percent.

¹H NMR(600MHz,CDCl₃)δ:8.23(s,1H),8.00-7.93(m,2H)，7.80(d,J＝8.8Hz,1H)，7.70-7.63(m,1H)，7.59-7.53(m,2H)，7.47(d,J＝2.2Hz,1H)，7.06(dd,J＝8.8,2.2Hz,1H)，3.89(s,3H)。

Synthesis of C.12.1H-pyrrolo [3,2-h ] quinoline-3-sulfonyl chloride XII-12

Step 1: synthesis of 1H-pyrrolo [3,2-H ] quinoline-3-sulfonic acid XII-12a

To a solution of 1H-pyrrolo [3,2-H ] quinoline (400mg, 2.3mmol) in pyridine (6mL) at 0 deg.C was added pyridine-sulfur trioxide complex (1.2g, 3.5 mmol). The reaction mixture was then heated at 120 ℃ for 2 hours with stirring, cooled to room temperature and evaporated to dryness. The beige solid was dissolved in water and the aqueous phase was washed with chloroform (3 ×). A precipitate formed upon standing in the aqueous portion and was filtered, washed with water and dried under vacuum at 35 ℃ to obtain 470mg of 1H-pyrrolo [3,2-H ] quinoline-3-sulfonic acid XII-12a as a beige solid.

Yield: 79 percent.

Basic LCMS method 1 (ES)⁺)：249(M+H)⁺100% purity.

Step 2: synthesis of 1H-pyrrolo [3,2-H ] quinoline-3-sulfonyl chloride XII-12

Phosphorus oxychloride (1.06g, 6.88mmol) was added dropwise to a solution of 1H-pyrrolo [3,2-H ] quinoline-3-sulfonic acid XII-12a (855mg, 3.44mmol) in acetonitrile (8.5mL) cooled to 0 ℃ under argon. The reaction mixture was then heated to 70 ℃ overnight with stirring. After cooling to room temperature, ice water was added carefully with vigorous stirring. A solid precipitated out and was filtered, washed with water and dried under vacuum at 35 ℃ to obtain 284mg of 1H-pyrrolo [3,2-H ] quinoline-3-sulfonyl chloride XII-12 as a beige solid.

Yield: 27 percent.

Basic LCMS method 1 (ES)⁺)：275(M+H)⁺Quenching aliquots with ethylamine prior to analysis

Synthesis of C.13.1H-benzo [ g ] indole-3-sulfonyl chloride XII-13

Step 1: synthesis of 1H-benzo [ g ] indole-3-sulfonic acid XII-13a

To a solution of 1H-benzo [ g ] indole (1g, 5.8mmol) in pyridine (16mL) at 0 deg.C was added pyridine-sulfur trioxide complex (1.38g, 8.7 mmol). The reaction mixture was then heated at 125 ℃ for 5 hours with stirring, cooled to room temperature and evaporated to dryness. The brown oil was diluted in water. After standing, a precipitate formed and was filtered, washed with water and dried under vacuum at 35 ℃ to obtain 1.4g of 1H-benzo [ g ] indole-3-sulfonic acid XII-13a as a beige solid.

Yield: 98 percent.

Basic LCMS method 1 (ES)^-)：246(M-H)^-

Step 2: synthesis of 1H-benzo [ g ] indole-3-sulfonyl chloride XII-13

Phosphorus oxychloride (76 μ L, 0.8mmol) was added dropwise to a solution of 1H-benzo [ g ] indole-3-sulfonic acid XII-13a (100mg, 0.4mmol) in acetonitrile (1mL) cooled to 0 ℃ under argon. The reaction mixture was then heated to 70 ℃ for 1 hour. After cooling to room temperature, ice water was added carefully with vigorous stirring. A solid precipitated out and was filtered, washed with water and dried under vacuum at 35 ℃ to give 65mg of 1H-benzo [ g ] indole-3-sulfonyl chloride XII-13 as a brown solid.

Yield: 60 percent.

Basic LCMS method 1 (ES)^-)：246(M-H)^-(corresponding sulfonic acids)

C.14.Synthesis of 5-bromo-6-chloro-1H-pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-14:

at 0 deg.C, to form 5-bromo-6-chloro-1H-pyrrolo [2,3-b]Pyridine (0.50g, 2.16mmol) in CH₃Adding ClSO into CN (10mL) solution₃H (5mL) and the reaction mixture was heated at 80 ℃ for 12 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was poured into ice H₂O (150mL), the precipitate was filtered and dried under vacuum to obtain 5-bromo-6-chloro-1H-pyrrolo [2,3-b ]]Pyridine-3-sulfonyl chloride (0.605g crude) as a brown solid.

This compound was used in the next reaction without further purification.

Basic LCMS method 2 (ES)^-)：309(M-H)^-(corresponding sulfonic acid), 97% purity.

C.15.Synthesis of 1- (benzenesulfonyl) -6-benzyloxy-pyrrolo [2,3-b ] pyridine-3-sulfonyl chloride XII-15:

treatment of 1- (phenylsulfonyl) -6-benzyloxy-pyrrolo [2,3-b ] with sulfur trioxide/DMF complex (1224mg, 8mmol)]Pyridine XI-4(570mg, 2mmol) in dichloromethane. The mixture was stirred at room temperature for 0.5h (TLC control showed no additional starting material but complete conversion to the desired sulfonic acid, eluent: pure dichloromethane). Thionyl chloride (thionyl chloride) (1.4mL, 20mmol) was then added and the resulting suspension stirred at room temperature for 22 h. The resulting clear solution was controlled by TLC (one spot of the expected product was observed, eluent: petroleum ether: ethyl acetate 80: 20). With saturated NaHCO₃The mixture was hydrolyzed with aqueous solution (75mL) and extracted with ethyl acetate (3X 30 mL). The combined organic extracts were extracted with MgSO₄Drying, filtration and concentration under reduced pressure gave 920mg of 1- (phenylsulfonyl) -6-benzyloxy-pyrrolo [2,3-b ]]Pyridine-3-sulfonyl chloride XII-15.

This compound was used in the next reaction without further purification.

Yield: and 64 percent.

¹H NMR(600MHz,DMSO-d₆)δ5.42(s,2H)，6.82(d,J＝8.5Hz,1H)，7.42-7.31(m,3H)，7.49(d,J＝9.1Hz,3H)，7.55(t,J＝7.9Hz,2H)，7.70(t,J＝7.5Hz,1H)，8.01-7.96(m,1H)，8.07(dd,J＝8.5,1.1Hz,2H)。

Example Compounds

D. Synthesis of Compounds of formula I

All of the compounds of the invention specifically disclosed herein are referred to as "I-x" where any "x" refers to a number that identifies the individual compound. Accordingly, the example compounds are referred to as I-1, I-2, I-3, etc. This is independent of whether any compound can also be described by any subformula (e.g. Formula II, III or IV etc.) herein.

D.1. Method A.Synthesis of 6-chloro-N- (2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide I-1

To a solution of XII-1(0.50g, 1.97mmol) in pyridine (10mL) was added X-1(0.18g, 1.25mmol) and DMAP (0.012g, 0.09 mmol). The reaction mixture was heated at 80 ℃ for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue is washed with H₂O (100mL), 1N HCl (50mL) and extracted with EtOAc (100 mL). Separating the organic layer with anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 40% EtOAc in hexane) to obtain 6-chloro-N- (2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide I-1(0.05g) as an off-white solid.

Yield: 7 percent.

Basic LCMS method 1 (ES)^-)：342(M-H)^-And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ7.25(dd,J＝8.31,1.47Hz,1H)，7.54(s,1H)，7.71-7.81(m,2H)，7.89(s,1H)，8.16(d,J＝2.93Hz,1H)，10.73(brs,1H)，12.22(brs,1H)。

The following compounds in table 4 can be synthesized according to a method similar to method a. Table 4:

6-chloro-N- (6-chloro-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonylamide I-2

Basic LCMS method 2 (ES)⁺)：378(M+H)⁺And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ7.25(d,J＝8.31Hz,1H)，7.54(s,1H)，7.75-7.84(m,1H)，7.94(t,J＝7.58Hz,1H)，8.16(brs,1H)，10.86(brs,1H)，12.22(brs,1H)。

6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-3

Basic LCMS method 2 (ES)^-)：388(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.53(s,3H)，7.23(dd,J＝8.56,1.71Hz,1H)，7.52(d,J＝1.96Hz,1H)，7.71(d,J＝9.29Hz,1H)，7.82(d,J＝8.80Hz,1H)，8.08(d,J＝2.93Hz,1H)，10.14(brs,1H)，12.12(brs,1H)。

6-chloro-N- (6-chloro-2-fluoro-5-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-4

Basic LCMS method 2 (ES)^-)：388(M-H)^-94% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.82(s,3H)，7.22-7.28(m,1H)，7.51-7.59(m,2H)，7.76(d,J＝8.80Hz,1H)，8.06(d,J＝2.93Hz,1H)，10.51(s,1H),12.17(brs,1H)。

6-chloro-N- (2, 5-difluoro-6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-5

Basic LCMS method 2 (ES)^-)：372(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.79(s,3H)，7.19(d,J＝8.80Hz,1H)，7.55-7.60(m,2H)，7.61-7.65(m,1H)，7.84(s,1H)，10.02(s,1H)，12.09(brs,1H)。

6-chloro-N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-indole-3-sulfonamide I-6

Basic LCMS method 2 (ES)^-)：384(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H)，3.82(s,3H)，7.19(dd,J＝8.56,1.71Hz,1H)，7.47(d,J＝10.27Hz,1H)，7.51(d,J＝1.47Hz,1H)，7.68(d,J＝8.31Hz,1H)，7.78(s,1H)，9.44(s,1H),11.95(brs,1H)。

6-chloro-N- (2, 5-difluoro-6-methylpyridin-3-yl) -1H-indole-3-sulfonamide I-7

Basic LCMS method 2 (ES)^-)：356(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ2.24(d,J＝2.8Hz,3H)，7.24(dd,J＝8.8Hz,1.6Hz,1H)，7.53(d,J＝2.4Hz,1H)，7.64(t,J＝8.8Hz,1H)，7.77(d,J＝8.8Hz,1H)，8.05(d,J＝2.4Hz,1H)，10.50(s,1H),12.15(brs,1H)。

6-chloro-N- (2-chloro-6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-8

Neutral LCMS method 3 (ES)⁺)：372(M+H)⁺95% purity.

¹H NMR(500MHz,DMSO-d₆)δ3.75(s,3H)，6.77(d,J＝8.51Hz,1H)，7.18(dd,J＝1.89,8.51Hz,1H)，7.48-7.56(m,2H)，7.65(d,J＝8.51Hz,1H)，7.77(d,J＝1.89Hz,1H)，10.90(s,1H)，12.10(brs,1H)。

6-chloro-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-9

Basic LCMS method 2 (ES)^-)：420(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.39(s,3H)，7.22(dd,J＝1.2,8.4Hz,1H)，7.52(d,J＝1.6Hz,1H)，7.58(t,J＝72.8Hz,1H)，7.70-7.77(m,2H)，7.94(d,J＝2.4Hz,1H)，9.85(brs,1H)，12.06(brs,1H)。

N- (5-bromo-3-methoxypyrazin-2-yl) -6-chloro-1H-indole-3-sulfonamide I-10

Basic LCMS method 2 (ES)⁺)：417(M+H)⁺And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.84(s,3H)，7.21(dd,J＝8.37,1.97Hz,1H)，7.54(d,J＝1.48Hz,1H)，7.82(s,1H)，7.89(d,J＝8.37Hz,1H)，8.09(s,1H)，10.93(brs,1H)，12.14(brs,1H)。

6-chloro-N- (5-chloro-3-methoxypyrazin-2-yl) -1H-indole-3-sulfonamide I-11

Basic LCMS method 2 (ES)⁺)：373(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.89(s,3H)，7.24(dd,J＝8.56,1.71Hz,1H)，7.53(d,J＝1.47Hz,1H)，7.82(s,1H)，7.95(d,J＝8.31Hz,1H)，8.14(d,J＝2.94Hz,1H)，10.97(s,1H)，12.15(brs,1H)。

6-chloro-N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-12

Basic LCMS method 2 (ES)^-)：416(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H)，4.42-4.46(m,1H)，4.50-4.55(m,1H)，4.62-4.66(m,1H)，4.75 4.78(m,1H)，7.20(dd,J＝8.80,1.96Hz,1H)，7.49-7.54(m,2H)，7.68(d,J＝8.31Hz,1H)，7.81(d,J＝2.45Hz,1H)，9.48(s,1H)，11.97(brs,1H)。

6-chloro-N- [6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-13

Basic LCMS method 2 (ES)⁺)：400(M+H)⁺And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H)，4.31-4.36(m,1H)，4.40-4.43(m,1H)，4.60-4.63(m,1H)，4.71-4.76(m,1H)，6.34(d,J＝8.31Hz,1H)，7.17(dd,J＝8.56,1.71Hz,1H)，7.44(d,J＝8.31Hz,1H)，7.51(s,1H)，7.65(d,J＝8.31Hz,1H)，7.72(s,1H)，9.21(s,1H)，11.92(brs,1H)。

6-chloro-N- (6-chloro-4-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-14

Alkaline LCMS formulaMethod 2 (ES)⁺)：372(M+H)⁺And 98% purity.

¹H NMR(400MHz,DMSO-d₆) δ 7.01(s,1H), 7.21(d, J ═ 8.31Hz,1H), 7.52(s,1H), 7.72(d, J ═ 8.31Hz,1H), 7.86(s,1H), 8.04(s,1H), 9.68(br s,1H), 12.04(br s,1H) (3H combined in solvent).

6-chloro-N- (2, 5-difluoro-6-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-33

Basic LCMS method 1 (ES)^-)：373(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.84(s,3H)，7.37(d,J＝8.3Hz,1H)，7.70(dd,J＝9.9,7.4Hz,1H)，8.05(d,J＝2.7Hz,1H)，8.10(d,J＝8.3Hz,1H)，10.12(s,1H),12.83(s,1H)。

6-chloro-N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-34

Basic LCMS method 1 (ES)^-)：385(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H)，3.85(s,3H)，7.36(d,J＝8.3Hz,1H)，7.53(d,J＝10.4Hz,1H)，7.95(s,1H)，8.11(d,J＝8.4Hz,1H)，9.59(s,1H)，12.69(s,1H)。

6-chloro-N- (6-chloro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-35

Basic LCMS method 1 (ES)^-)：371(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.44(s,3H)，7.03(d,J＝8.0Hz,1H)，7.37(d,J＝8.3Hz,1H)，7.63(d,J＝8.0Hz,1H)，8.05(s,1H)，8.19(d,J＝8.3Hz,1H)，9.88(s,1H)，12.78(s,1H)。

6-chloro-N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-36

Basic LCMS method 1 (ES)^-)：417(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(d,J＝1.4Hz,3H)，4.45(t,J＝4.4Hz,1H)，4.53(t,J＝4.1Hz,1H)，4.68-4.62(m,1H)，4.80-4.74(m,1H)，7.35(dd,J＝8.3,1.4Hz,1H)，7.56(dd,J＝10.4,1.4Hz,1H)，7.96(d,J＝1.4Hz,1H)，8.10(dd,J＝8.4,1.4Hz,1H)，9.8(s,1H)，12.6(s,1H)。

6-chloro-N- [6- (difluoromethoxy) -2-methoxy-3-pyridinyl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-37

Basic LCMS method 1 (ES)^-)：403(M-H)^-And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.34(s,3H)，6.58(d,J＝8.2Hz,1H)，7.36(d,J＝8.3Hz,1H)，7.58(t,1H)，7.65(d,J＝8.2Hz,1H)，7.96(s,1H)，8.13(d,J＝8.3Hz,1H)，9.68(s,1H)，12.72(s,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-38

Basic LCMS method 2 (ES)⁺)：418(M+H)⁺，94％And (4) purity.

¹H NMR(400MHz,DMSO-d₆)δ3.28(s,3H)4.43(td,J＝14.92,3.91Hz,2H)6.17-6.46(m,1H)6.39(d,J＝8.31Hz,1H)7.18(dd,J＝8.56,1.71Hz,1H)7.46(d,J＝8.31Hz,1H)7.51(d,J＝1.96Hz,1H)7.66(d,J＝8.80Hz,1H)7.74(s,1H)9.28(brs,1H)11.93(brs,1H)。

6-chloro-N- [2- (2, 2-difluoroethoxy) -6-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-39

Basic LCMS method 2 (ES)⁺)：418(M+H)⁺96% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.74(s,3H)4.05(td,J＝14.31,4.16Hz,2H)5.61-5.95(m,1H)6.39(d,J＝8.31Hz,1H)7.12-7.21(m,1H)7.48(d,J＝8.31Hz,1H)7.52(s,1H)7.65(d,J＝8.80Hz,1H)7.77(s,1H)9.36(brs,1H)11.95(brs,1H)。

6-chloro-N- [6- (difluoromethoxy) -4-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-40

Basic LCMS method 2 (ES)⁺)：404(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.28(s,3H)6.56(s,1H)7.20(dd,J＝8.61,1.72Hz,1H)7.52(d,J＝1.48Hz,1H)7.63(t,J＝74Hz,1H)7.69(d,J＝8.37Hz,1H)7.79(d,J＝2.46Hz,1H)7.85(s,1H)9.49(s,1H)11.99(brs,1H)。

6-chloro-N- (6-cyclopropyl-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide I-41

Basic LCMS method 2 (ES)⁺)：384(M+H)⁺And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ0.77-0.79(m,2H)0.93-1.00(m,2H)2.11-2.14(m,1H)7.22(d,J＝8.31Hz,1H)7.53(s,1H)7.59-7.65(m,1H)7.73(d,J＝8.31Hz,1H)8.04(d,J＝2.93Hz,1H)10.40(s,1H)12.16(brs,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-42

Basic LCMS method 2 (ES)⁺)：436(M+H)⁺94% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.30(s,3H)4.54(td,J＝14.92,3.42Hz,2H)6.20-6.51(m,1H)7.20(dd,J＝8.31,1.96Hz,1H)7.52(d,J＝1.96Hz,1H)7.55(d,J＝10.27Hz,1H)7.70(d,J＝8.31Hz,1H)7.83(s,1H)9.55(brs,1H)11.99(brs,1H)。

6-chloro-N- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-43

Basic LCMS method 2 (ES)⁺)：466(M+H)⁺95% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.23(s,3H)4.09-4.15(m,2H)4.37-4.44(m,2H)6.68(t,J＝76Hz,1H)7.18(dd,J＝8.37,1.48Hz,1H)7.45-7.51(m,2H)7.66(d,J＝8.86Hz,1H)7.80(s,1H)9.54(brs,1H)11.96(brs,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -2, 5-difluoropyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-44

Basic LCMS method 1 (ES)^-)：423(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆)δ4.52(td,J＝15.0,3.3Hz,2H)，6.36(tt,J＝54.1,3.3Hz,1H)，7.37(d,J＝8.3Hz,1H)，7.79(dd,J＝9.8,7.4Hz,1H)，8.21-7.92(m,2H)，10.24(s,1H)，12.85(s,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-45

Basic LCMS method 1 (ES)^-)：417(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.28(s,3H)，4.45(td,J＝14.9,3.6Hz,2H)，6.51-6.12(m,2H)，7.34(d,J＝8.3Hz,1H)，7.51(d,J＝8.2Hz,1H)，7.90(s,1H)，8.08(d,J＝8.3Hz,1H)，12.66(s,1H)，9.47(s,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-46

Basic LCMS method 1 (ES)^-)：435(M-H)^-And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.28(s,3H)，4.56(td,J＝14.8,3.5Hz,2H)，6.37(t,1H)，7.37(d,J＝8.4Hz,1H)，7.62(d,J＝10.2Hz,1H)，7.99(s,1H)，8.13(d,J＝8.3Hz,1H)，9.71(s,1H)，12.72(s,1H)。

6-chloro-N- (6-cyclopropyl-2, 5-difluoropyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-47

Basic LCMS method 1 (ES)^-)：383(M-H)^-95% purity.

¹H NMR(400MHz,DMSO-d₆)δ1.12-0.64(m,4H)，2.24-2.02(m,1H)，7.38(d,J＝8.4Hz,1H)，7.66(dd,J＝9.5,7.5Hz,1H)，8.25-8.11(m,2H)，10.46(s,1H)，12.89(s,1H)。

6-chloro-N- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-48

Basic LCMS method 1 (ES)^-)：465(M-H)^-94% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.24(s,3H)，4.30(d,J＝122.2Hz,4H)，6.71(s,1H)，8.25-7.18(m,4H)，9.65(s,1H)，12.63(s,1H)。

6-chloro-N- (5-fluoro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-49

Basic LCMS method 1 (ES)^-)：355(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.51(s,3H)，7.38(d,J＝8.3Hz,1H)，7.57(dd,J＝9.4,2.8Hz,1H)，7.85(d,J＝2.8Hz,1H)，8.31-8.16(m,2H)，10.07(s,1H)，12.83(s,1H)。

6-chloro-N- (6-cyclopropyl-5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-50

Basic LCMS method 2 (ES)⁺)：396(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ0.81-0.87(m,2H)0.89-0.94(m,2H)2.08-2.10(m,1H)3.36(s,3H)7.20(dd,J＝8.80,1.47Hz,1H)7.41(d,J＝10.27Hz,1H)7.51(s,1H)7.75(d,J＝8.80Hz,1H)7.95(d,J＝2.45Hz,1H)9.68(s,1H)12.04(brs,1H)。

N- [6- (2, 2-Difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethoxy) -1H-indole-3-sulfonamide I-51

Basic LCMS method 2 (ES)⁺)：468(M+H)⁺And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.29(s,3H)4.50-4.60(m,2H)6.22-6.52(m,1H)7.00-7.05(m,1H)7.20(t,J＝74,1H)7.25(s,1H)7.55(d,J＝10.34Hz,1H)7.71(d,J＝8.86Hz,1H)7.83(d,J＝2.46Hz,1H)9.54(s,1H)11.95(brs,1H)。

N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [3,2-H ] quinoline-3-sulfonamide I-68

Basic LCMS method 1 (ES)^-)：437(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆) δ 3.32(s,3H) under solvent peak (solvent peak), 8.04-7.30(m,6H), 8.45(d, J ═ 8.2Hz,1H), 8.92(d, J ═ 4.5Hz,1H), 9.91(s,1H),13.17(s, 1H).

N- [6- (2, 2-Difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [3,2-H ] quinoline-3-sulfonamide I-69

Basic LCMS method 1 (ES)^-)：451(M-H)^-94% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.25(s,3H)，4.51(td,J＝14.8,3.5Hz,2H)，6.33(t,J＝3.5Hz,1H)，7.71-7.54(m,3H)，7.80(s,1H)，7.89(d,J＝8.7Hz,1H)，8.45(dd,J＝8.3,1.6Hz,1H)，8.92(dd,J＝4.3,1.6Hz,1H)，9.63(s,1H)，13.10(s,1H)。

N- (2, 6-Dimethoxypyridin-3-yl) -1H-benzo [ g ] indole-3-sulfonamide I-70

Neutral LCMS method 3 (ES)⁺)：384(M+H)⁺And 98% purity.

¹H NMR(500MHz,DMSO-d₆)δ3.21(s,3H)，3.70(s,3H)，6.28(d,J＝8.3Hz,1H)，7.52-7.38(m,2H)，7.65-7.54(m,2H)，7.83-7.69(m,2H)，8.01-7.86(m,1H)，8.45-8.32(m,1H)，9.13(s,1H)，12.71(s,1H)。

5-bromo-6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-71

Basic LCMS method 2 (ES)⁺)：515(M+H)⁺94% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.29(s,3H)4.55(td,J＝14.80,3.18Hz,2H)6.22-6.54(m,1H)7.64(d,J＝10.27Hz,1H)8.08(s,1H)8.47(s,1H)9.80(brs,1H)12.90(brs,1H)。

D.2.6 Synthesis of chloro-N- (6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-15

In a vial, a solution of 6-chloro-indole (630mg, 4.1mmol) in acetonitrile (25.2mL) was stirred in an ice bath, chlorosulfonic acid (714 μ l, 10.7mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. The ice bath was removed and the reaction mixture was heated to 60 ℃ for 1.5 hours. After cooling to room temperature, pyridine (54.6mL) was added and the solution turned yellow. In a second sealed vial, 6-methoxypyridin-3-amine (37.2mg, 0.3mmol) was weighed and an aliquot of the previous solution (2.8mL, 0.15mmol) was added. The reaction mixture was stirred at 80 ℃ for 2 hours and then evaporated in a centrifugal evaporator. The purification residue was checked by reverse phase chromatography with MS in basic mode to obtain 21.8mg of 6-chloro-N- (6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-15.

Yield: 42 percent.

Basic LCMS method 1 (ES)^-)：336(M-H)^-100% purity.

D.3. Method B Synthesis of N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide I-16

Step 1: synthesis of 1- (benzenesulfonyl) -N- [6- (difluoromethoxy) -5-fluoro-2-methoxy-3-pyridyl ] -6- (difluoromethyl) indole-3-sulfonamide I-16a

In a sealed vial, 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-amine X-8(150mg, 0.49mmol) was dissolved in pyridine (3mL) under argon. 1- (benzenesulfonyl) -6- (difluoromethyl) indole-3-sulfonyl chloride XII-6(290mg, 0.71mmol) was added at 0 deg.C, followed by stirring at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). The organic phase was washed with MgSO₄Dried and evaporated. The residue was purified by silica flash chromatography (eluting with a gradient of DCM and methanol from 100/0 to 95/5) to give 310mg of 1- (benzenesulfonyl) -N- [6- (difluoromethoxy) -5-fluoro-2-methoxy-3-pyridinyl]-6- (difluoromethyl) indole-3-sulfonamide I-16a as a white solid.

Yield: 75 percent.

Basic LCMS method 1 (ES)^-)：576(M-H)^-100% purity.

Step 2: synthesis of N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide I-16

In a sealed tube, 1- (benzenesulfonyl) -N- [6- (difluoromethoxy) -5-fluoro-2-methoxy-3-pyridyl]-6- (difluoromethyl) indole-3-sulfonamide I-16a (310mg, 0.54mmol) was dissolved in THF (4 mL). Tetrabutylammonium fluoride (1.3mL, 1M aqueous solution, 1.3mmol) was added and the reaction mixture was stirred at 90 ℃ overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). The organic phase was washed with MgSO₄Dried and evaporated. The residue was purified by flash chromatography on silica (eluting with DCM/MeOH 95/5) to give 170mg of N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl]-6- (difluoromethyl) -1H-indole-3-sulfonamide I-16 as a bright yellow solid.

Yield: 58 percent.

Basic LCMS method 1 (ES)^-)：436(M-H)^-And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.37(s,3H)，7.12(t,J＝56.0Hz,1H)，7.80-7.32(m,4H)，7.89(d,J＝8.3Hz,1H)，8.04(s,1H)，9.84(s,1H)，12.22(s,1H)。

The following compounds in table 5 can be synthesized according to a method similar to method B. Table 5:

6-chloro-N- (5-chloro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-17

Basic LCMS method 1 (ES)^-)：370(M-H)^-100% purity.

N- (5-bromopyrazin-2-yl) -6-chloro-1H-indole-3-sulfonamide I-18

Basic LCMS method 1 (ES)^-)：385(M-H)^-And 98% purity.

6-chloro-N- (6-cyanopyridin-3-yl) -1H-indole-3-sulfonamide I-19

Basic LCMS method 1 (ES)^-)：331(M-H)^-And 98% purity.

N- (6-bromopyridin-3-yl) -6-chloro-1H-indole-3-sulfonamide I-20

Basic LCMS method 1 (ES)^-)：384(M-H)^-And 98% purity.

6-chloro-N- (6-iodopyridin-3-yl) -1H-indole-3-sulfonamide I-21

Basic LCMS method 1 (ES)^-)：432(M-H)^-100% purity.

6-chloro-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-22

Basic LCMS method 1 (ES)^-)：421(M-H)^-And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.37(s,J＝1.2Hz,3H)，7.37(d,J＝8.4,1.2Hz,1H)，7.77-7.40(t,1H)，7.77(d,J＝4.1Hz,1H)，8.09(s,J＝2.1Hz,1H)，8.18(d,J＝8.3,1.2Hz,1H)，9.95(s,1H)，12.77(s,1H)。

6-chloro-N- (6-chloro-5-fluoropyridin-3-yl) -1H-indole-3-sulfonamide I-23

Neutral LCMS method 3 (ES)⁺)：360(M+H)⁺And 99% purity.

¹H NMR(500MHz,DMSO-d₆)δ7.25(dd,J＝1.93,8.53Hz,1H)，7.52(d,J＝1.83Hz,1H)，7.54(dd,J＝2.38,10.09Hz,1H)，7.78(d,J＝8.62Hz,1H)，7.97(d,J＝2.38Hz,1H)，8.22(d,J＝2.93Hz,1H)，10.97(br s,1H)，12.22(br s,1H)。

6-chloro-N- (6-chloropyridin-3-yl) -1H-indole-3-sulfonamide I-24

Neutral LCMS method 3 (ES)⁺)：342(M+H)⁺95% purity.

¹H NMR(500MHz,DMSO-d₆)δ7.23(dd,J＝1.83,8.62Hz,1H)，7.33(d,J＝8.62Hz,1H)，7.46-7.57(m,2H)，7.76(d,J＝8.44Hz,1H)，8.01-8.14(m,2H)，10.62(br s,1H)，12.15(br s,1H)。

6-chloro-N- (6-chloro-4-fluoropyridin-3-yl) -1H-indole-3-sulfonamide I-25

Neutral LCMS method 3 (ES)⁺)：360(M+H)⁺And 97% purity.

¹H NMR(500MHz,DMSO-d₆)δ7.22(dd,J＝1.93,8.53Hz,1H)，7.53(d,J＝1.83Hz,1H)，7.54(d,J＝9.54Hz,1H)，7.69(d,J＝8.62Hz,1H)，7.96(d,J＝2.75Hz,1H)，8.22(d,J＝9.90Hz,1H)，10.35(br.s.,1H)，12.14(br.s.,1H)。

6-chloro-N- (4, 6-dichloropyridin-3-yl) -1H-indole-3-sulfonamide I-26

Neutral LCMS method 3 (ES)⁺)：376(M+H)⁺96% purity.

¹H NMR(500MHz,DMSO-d₆)δ7.19(d,J＝8.4Hz,1H)，7.65(d,J＝8.6Hz,1H)，7.53(s,1H)，7.68(s,1H)，7.90(d,J＝4.0Hz,1H)，8.22(s,1H)，10.17(s,1H)，12.13(s,1H)。

N- (6-chloro-2-methoxypyridin-3-yl) -6- (difluoromethyl) -1H-indole-3-sulfonamide I-27

Basic LCMS method 1 (ES)^-)：386(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ7.26-6.95(m,2H)，7.40-7.33(m,1H)，3.43(s,3H)，7.61(d,J＝8.1Hz,1H)，7.69(d,J＝1.5Hz,1H)，7.90(dd,J＝8.4,0.8Hz,1H)，8.00(s,1H)，9.78(s,1H)，12.21(s,1H)。

N- (6-chloro-2-methoxypyridin-3-yl) -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-28

Basic LCMS method 1 (ES)^-)：387(M-H)^-And 97% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.40(s,3H),7.27-6.63(m,2H),7.77-7.35(m,2H),8.27(d,J＝73.6Hz,2H),9.90(s,1H),12.89(s,1H)。

N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-29

Basic LCMS method 1 (ES)^-)：405(M-H)^-And 97% purity.

N- [6- (2, 2-Difluoroethoxy) -2, 5-difluoro-3-pyridinyl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-30

Basic LCMS method 1 (ES)^-)：439(M-H)^-And 99% purity.

N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-31

Basic LCMS method 1 (ES)^-)：437(M-H)^-And 99% purity.

N- [6- (2, 2-Difluoroethoxy) -2, 5-Difluoropyridin-3-yl ] -6- (Difluoromethyl) -1H-indole-3-sulfonamide I-52

Basic LCMS method 1 (ES)^-)：438(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆)δ4.51(td,J＝15.1,3.3Hz,2H)，6.53-6.17(m,1H)，7.14(t,J＝56.1Hz,1H)，7.38(d,J＝8.4Hz,1H)，7.80-7.65(m,2H)，7.83(d,J＝8.3Hz,1H)，8.04(d,J＝2.9Hz,1H)，10.17(s,1H)，12.31(s,1H)。

N- [6- (2, 2-Difluoroethoxy) -2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-53

Basic LCMS method 1 (ES)^-)：433(M-H)^-100% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.21(s,3H),4.43(td,J＝14.9,3.6Hz,2H)，6.48-6.13(m,2H)，7.10(d,J＝55.1Hz,1H)，7.53(dd,J＝14.9,8.2Hz,2H)，8.03(s,1H)，8.21(d,J＝8.2Hz,1H)，9.46(s,1H)，12.77(s,1H)。

N- [6- (2, 2-Difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-54

Basic LCMS method 1 (ES)^-)：451(M-H)^-95% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.23(s,3H)，4.54(td,J＝14.8,3.5Hz,2H)，6.36(tt,J＝54.5,3.6Hz,1H)，7.04(t,J＝55.1Hz,1H)，7.60(dd,J＝17.0,9.2Hz,2H)，8.13(s,1H)，8.27(d,J＝8.2Hz,1H)，9.72(s,1H)，12.83(s,1H)。

6- (difluoromethyl) -N- [ 5-fluoro-6- (2-fluoroethoxy) -2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-55

Basic LCMS method 1 (ES)^-)：433(M-H)^-And 99% purity.

6- (difluoromethyl) -N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-56

Basic LCMS method 1 (ES)^-)：401(M-H)^-100% purity.

6- (difluoromethyl) -N- (2, 5-difluoro-6-methylpyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-57

Basic LCMS method 1 (ES)^-)：373(M-H)^-And 98% purity.

N- [6- [2- (difluoromethoxy) ethoxy ] -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-58

Basic LCMS method 1 (ES)^-)：481(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.18(s,3H),4.28(d,J＝120.0Hz,4H)，7.24-6.35(m,2H)，7.57(d,J＝9.2Hz,2H)，8.11(s,1H)，8.24(d,J＝8.1Hz,1H)，9.66(s,1H)，12.81(s,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -7-fluoro-1H-indole-3-sulfonamide I-59

Basic LCMS method 1 (ES)^-)：452(M-H)^-95% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.31(s,3H)，4.78-4.42(m,2H)，6.60-6.09(m,1H)，7.30(t,J＝7.6Hz,1H)，7.58(dt,J＝22.5,9.7Hz,2H)，7.92(s,1H)，9.76(s,1H)，12.7(s,1H)。

N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methyl-1H-indole-3-sulfonamide I-60

Basic LCMS method 1 (ES)^-)：400(M-H)^-And 98% purity.

¹H NMR(400MHz,DMSO-d₆)δ2.39(s,3H)，3.45(s,3H)，7.00(d,J＝8.1Hz,1H)，7.25(s,1H)，7.74-7.56(m,3H)，7.84(d,J＝2.9Hz,1H)，9.71(s,1H)，11.82(s,1H)。

6-chloro-N- (2, 6-dimethoxypyridin-3-yl) -1H-indole-3-sulfonamide I-61

Neutral LCMS method 3 (ES)⁺)：368(M+H)⁺And 99% purity.

¹H NMR(500MHz,DMSO-d₆)δ3.24(s,3H)，3.73(s,3H)，6.28(d,J＝8.3Hz,1H)，7.17(dd,J＝8.6,1.9Hz,1H)，7.41(d,J＝8.3Hz,1H)，7.51(d,J＝1.9Hz,1H)，7.66(d,J＝8.6Hz,1H)，7.69(s,1H)，9.16(s,1H)，11.89(s,1H)。

N- [6- (2, 2-Difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6- (difluoromethyl) -1H-indole-3-sulfonamide I-62

Basic LCMS method 1 (ES)^-)：450(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.25(s,3H)，4.52(td,J＝14.8,3.6Hz,2H)，6.35(tt,J＝54.5,3.5Hz,1H)，7.12(t,J＝56.1Hz,1H)，7.86-7.29(m,4H)，7.95(d,J＝2.2Hz,1H)，9.56(s,1H)，12.17(s,1H)。

N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methoxy-1H-indole-3-sulfonamide I-63

Basic LCMS method 1 (ES)^-)：414(M-H)^-95% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.45(s,3H)，3.77(s,3H)，6.87-6.76(m,1H)，6.93(s,1H)，7.76-7.33(m,3H)，7.78(d,J＝2.9Hz,1H)，9.73(s,1H)，11.74(s,1H)。

N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -6-methoxy-1H-indole-3-sulfonamide I-64

Basic LCMS method 1 (ES)^-)：430(M-H)^-95% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.36(s,3H),3.77(s,3H)，4.54(td,J＝14.9,3.6Hz,2H)，6.36(t,J＝3.5Hz,1H)，6.80(dd,J＝8.8,2.3Hz,1H)，6.93(d,J＝2.3Hz,1H)，7.53(dd,J＝19.8,9.6Hz,2H)，7.66(d,J＝2.8Hz,1H)，9.42(s,1H)，11.67(s,1H)。

6-chloro-N- [6- (2, 2-difluoroethoxy) -2, 5-difluoropyridin-3-yl ] -1H-indole-3-sulfonamide I-67

Basic LCMS method 1 (ES)^-)：422(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ4.49(t,J＝14.8Hz,2H)，6.34(t,J＝54.4Hz,1H)，7.20(d,J＝8.6Hz,1H)，7.52(s,1H)，7.70(d,J＝8.5Hz,2H)，7.88(s,1H)，10.14(s,1H)，12.03(s,1H)。

N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -6-phenylmethoxy-1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-72

Neutral LCMS method 3 (ES)⁺)：463(M+H)⁺96% purity.

¹H NMR(500MHz,DMSO-d₆)δ3.56(s,3H),5.36(s,2H)，6.79(d,J＝8.6Hz,1H)，7.30(t,J＝7.3Hz,1H)，7.36(t,J＝7.3Hz,2H)，7.45(d,J＝6.9Hz,2H)，7.70(d,J＝9.2Hz,1H)，7.90(d,J＝2.7Hz,1H)，8.11(d,J＝8.5Hz,1H)，10.07(s,1H)，12.40(s,1H)。

D.4.Synthesis of 6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide I-32

In a sealed vial, 1- (benzenesulfonyl) -6-chloro-pyrrolo [2,3-b ] is added]Pyridine-3-sulfonyl chloride XII-4(100mg, 0.26mmol) was dissolved in pyridine (4 mL). 6-chloro-5-fluoro-2-methoxy-pyridin-3-amine X-3(67mg, 0.38mmol) was added, followed by stirring at 70 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (twice). The organic phase is over MgSO₄Dried and evaporated. LCMS by basic preparative method 1 purificationThe residue was taken up to give 11mg of 6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-pyrrolo [2,3-b ]]Pyridine-3-sulfonamide I-32, as a pale yellow solid.

Yield: 11 percent.

Basic LCMS method 1 (ES)^-)：389(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.63(s,3H)，7.39(d,J＝8.4Hz,1H)，7.98(d,J＝9.0Hz,1H)，8.29(dd,J＝18.4,5.6Hz,2H)，11.17(s,1H)，12.87(s,1H)。

D.5.6 Synthesis of cyano-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-65

Step 1: synthesis of 6-bromo-N- (6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-65a

To a solution of 6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-amine X-20(0.30g, 1.34mmol) in pyridine (8mL) was added 6-bromo-1H-indole-3-sulfonyl chloride II-2(1.58g, 5.35mmol) portionwise at 0 deg.C for 10 min, then DMAP (0.02g, 0.13mmol) was added at 0 deg.C and the reaction mixture was heated at 90 deg.C for 20H. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was triturated with 2N HCl (10mL) and triturated with H₂O (70mL) was diluted and extracted with EtOAc (3X 35 mL). The organic layer was separated, washed with brine (2X 60mL), over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 30% EtOAc in hexane) to give 6-bromo-N- (6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3 yl) -1H-indole-3-sulfonamide I-65a (0.42g) as an off-white solid.

Yield: 62 percent.

Basic LCMS method 2 (ES)⁺)：481(M+H)⁺95% purity.

Step 2: synthesis of 6-cyano-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-65

To a solution of 6-bromo-N- (6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-65a (0.20g, 0.40mmol) in DMF (6mL) was added Zn (CN)₂(0.14g, 1.19mmol) and the reaction mixture purged with argon for 15 minutes. Adding Pd₂(dba)₃(0.02g,0.02mmol) and 1, 1' -bis (diphenylphosphino) ferrocene (0.02g,0.04mmol), and the reaction mixture was heated in a microwave at 110 ℃ for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture is washed with H₂Diluted O (80mL) and extracted with EtOAc (3X 40 mL). The organic layer was separated, washed with brine (2X 60mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 35% EtOAc in hexane) to obtain 6-cyano-N- [6- (2, 2-difluoroethoxy) -5-fluoro-2-methoxypyridin-3-yl]-1H-indole-3-sulfonamide I-65(0.077g, 45%) as an off-white solid.

Yield: 45 percent.

Basic LCMS method 2 (ES)^-)：425(M-H)^-And 99% purity.

¹H NMR(400MHz,DMSO-d₆)δ3.21(s,3H)4.53(td,J＝14.67,3.42Hz,2H)6.20-6.50(m,1H)7.54(dd,J＝8.31,0.98Hz,1H)7.59(d,J＝10.27Hz,1H)7.86(d,J＝8.31Hz,1H)7.99(s,1H)8.04(s,1H)9.68(brs,1H)12.41(brs,1H)。

D.6.6 Synthesis of 6-cyano-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-66

Step 1: synthesis of 6-bromo-N- (6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-66 a:

to a solution of 6- (difluoromethoxy) -5-fluoro-2-methoxy-pyridin-3-ylamine X-8(0.10g,0.47mmol) in pyridine (2mL) at 0 deg.C6-bromo-1H-indole-3-sulfonyl chloride XII-2(0.44g, 1.50mmol) was added portionwise for 20 minutes, followed by DMAP (0.006g, 0.05mmol) at the same temperature and the reaction mixture was heated at 100 ℃ for 18 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under vacuum. The residue was triturated with 2N HCl (5mL) and triturated with H₂O (10mL) was diluted and extracted with EtOAc (3X 25 mL). The organic layer was separated, washed with brine (2X 30mL), and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh, 200 mesh, 40% EtOAc in hexane) to afford 6-bromo-N- (6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-66a (0.15g) as an off-white solid.

Yield: and 63 percent.

Basic LCMS method 2 (ES)^-)：46(M-H)^-And 92% purity.

Step 2: 6-cyano-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-indole-3-sulfonamide I-66:

to a solution of 6-bromo-N- (6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide I-66a (0.09g, 0.18mmol) in DMF (2mL) was added CuCN (0.03g, 0.36mmol) and the reaction mixture was purged with argon for 20 min, then added Pd (PPh)₃)₄(0.02g,0.02 mmol). The reaction mixture was purged with argon for 5 minutes and heated at 110 ℃ for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion, the reaction mixture is washed with H₂O (20mL) and EtOAc (20mL) were diluted and filtered through a pad of celite. The organic layer was separated and the aqueous layer was extracted with EtOAc (3X 15 mL). The combined organic layers were washed with brine (2X 20mL) and dried over anhydrous Na₂SO₄Dried and concentrated under vacuum. The crude product obtained was purified by column chromatography (silica, 100 mesh 200, 50% EtOAc in hexane) to obtain 6-cyano-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl]-1H-indole-3-sulfonamide I-66(0.025g) as an off-white solid.

Yield: 33 percent.

Basic LCMS method2(ES^-)：411(M-H)^-96% purity.

¹H NMR(400MHz,DMSO-d₆) δ 7.53-7.55(m,1H)7.55(t, J ═ 72Hz,1H)7.73-7.77(m,1H)7.91(d, J ═ 8.31Hz,1H)7.99(s,1H)8.13(s,1H)9.94(brs,1H)12.45(brs,1H) (3H combined in solvent peaks).

Test examples, and Ca is reported in table 6 below²⁺And activity in cAMP assays.

B. Biology/pharmacology:

B-I. cell culture

GPR17 recombinant cell line:

Flp-In T-REx CHO cells stably expressing the human GPR17 receptor (CHO hGPR17) from Evi Kostenis's laboratory (Bonn university, Germany) at 37 ℃ with 5% CO₂Is cultured in a humid atmosphere. Cells were grown in DMEM supplemented with the nutrient mixture F-12 of hygromycin B (500. mu.g/ml) and blasticidin (30. mu.g/ml). Expression of the Flp-In locus was induced by treatment with doxycycline (1. mu.g/ml) for 16-20 hours prior to assay.

Primary oligodendrocytes (Primary oligodendrocytes):

primary Oligodendrocyte Precursor Cells (OPCs) were isolated from the forebrain of Wistar rat pups on postnatal days 0 to 2. The brain was dissociated mechanically using a syringe and two different hollow needles (first 1.2X 40 and then 0.60X 30). The pellet-free cell suspension was filtered through a 70- μm cell strainer and plated in poly-D-lysine coated 75-cm in DMEM²Flasks were supplemented with 10% (v/v) heat-inactivated fetal bovine serum, penicillin (100 units/ml) and streptomycin (0.1mg/ml) and the medium was changed every other day. At 37 ℃ and 5% CO₂After 8 to 11 days in a humid atmosphere, the mixed culture was shaken at 240rpm for 14-24 hours to separate OPC from astrocytes (astrocytes) and microglia (microglia). To further enrich for OPC, the suspension was spread on uncoated petri dishes for 45 minutes. OPC was then seeded into poly-L-ornithine coated disks and maintained at 37 ℃ with 5% CO₂Cell proliferating neurons in humid atmosphere (N)eurobasal) medium supplemented with 2% (v/v) B27, 2mM GlutaMAX, 100 units/ml penicillin, 0.1mg/ml streptomycin, 10ng/ml PDGF-AA and 10ng/ml basic FGF, the medium being changed every other day.

B-II: functional in vitro GPR17 assay

B-II-A: calcium mobility function assay

GPR17 is a G protein coupled receptor. Activation of GPR17 triggers Gq-type G protein signaling, resulting in calcium endoplasmic reticulum (Ca)²⁺) Storage and release in the cytoplasm, which can use Calcium 5dye (Calcium 5dye) (cytoplasmic Ca)²⁺Amount of fluorescent indicator dye). In Ca²⁺The compounds of the invention are evaluated in an assay or GPR17 cAMP assay, described further below. Some representative examples were measured in two activity tests, as shown in table 6 below.

Ca²⁺Description of the measurement:

CHO hpgpr 17 was thawed and seeded at a density of 20,000 cells per well in black 384-well plate with a clear bottom. Cells were incubated at 37 ℃ with 5% CO₂Overnight in a humid atmosphere. 16 to 20 hours after inoculation, with calcium 5dye (cytoplasmic Ca) according to the manufacturer's instructions²⁺Indicator fluorescent dye) was loaded into CHO gpr17 for 60 minutes. Recording of Ca relative to the cytoplasm at room temperature over time in a FLIPR Tetra reader²⁺Concentration of fluorescent signal. Cells are first incubated at room temperature with increasing concentrations of test compound (usually 10)^-11M to 10^-6M) was incubated for 30 minutes in HBSS Hepes buffer pH 7.4. Then, 50nM MDL29,951(GPR17 agonist) was added to the cells. Measuring the inhibitory effect of test compounds at different concentrations and determining the pIC obtained₅₀. All cultures were duplicate and the results were compared to the concentration response curves for GPR17 agonist and antagonist reference compounds. Analysis and curve fitting were performed at ActivityBase XE using XLfit 4 parametric logistic equation y ═ a + ((B-a)/(1+ ((C/x) ^ D))), where A, B, C and D represent minimum y, maximum y, IC, respectively₅₀And a slope.

Ca²⁺Results of mobility assays:

when in Ca²⁺The compounds of the examples typically exhibit a pIC of greater than or equal to 6.5 when tested in a mobility assay₅₀A value; more preferably greater than or equal to 7.5, and even more preferably greater than or equal to 8.5. The activity of the compounds of the examples tested is described in table 6 below in section B-IIB. The activity ranges A, B and C refer to Ca²⁺pIC in assay₅₀The values, as shown below: "A": pIC₅₀ 6.5≤x<7.5，“B”：pIC₅₀ 7.5≤x<8.5，“C”：8.5≤pIC₅₀。

Measurement of cAMP accumulation function in B-IIB

GPR17 activation also recruits Gi type G protein signaling, resulting in a decrease in intracellular cyclic adenosine monophosphate (cAMP). Changes in intracellular cAMP can be measured using the HTRF cAMP kinetic assay kit from CisBio (Codolet, france). The assay is based on competition between native cAMP produced by the cells and cAMP labeled with dye d2 using homogeneous time-resolved fluorescence technology (HTRF). Tracer binding was determined by anti-cAMP antibody labeled with cryptate (cryptate).

Description of cAMP measurement

CHO gpr17 was isolated with EDTA-containing PBS and dispensed into black 384-well plates, 5,000 cells per well. Cells were first cultured for 30 minutes at room temperature in HBSS Hepes (pH 7.4) containing vehicle (vehicle) or test GPR17 antagonist/inverse agonist compounds at different concentrations. Thereafter, MDL29,951GPR17 agonist (typically 10) was added to the vehicle and at the concentration of each test GPR17 antagonist/inverse agonist compound^-5M to 10^-10M), final volume of 20 μ L HBSS Hepes buffer (pH 7.4) containing 1% DMSO, 5 μ M forskolin (forskolin) and 0.1mM IBMX. After incubation at room temperature for 60 minutes, the d2 detection reagent and cryptate (cryptate) reagent were added to 10 μ L of cell lysis buffer, respectively, according to the manufacturer's instructions, the reaction was stopped and the cells lysed. After 60 minutes of incubation, changes in cAMP concentration were measured using an Envision disk reader excited with a laser according to the manufacturer's instructions. By repeatingCulturing. Data were analyzed using GraphPad Prism software using the 4-parameter logistic equation to measure mdl29,951pec in the absence and presence of GPR17 antagonist/inverse agonist test compounds₅₀. Plotting Dose Ratio (DR) against antagonist concentration, the Schild analysis provides an estimated affinity pA for GPR17 antagonist/inverse agonist test compounds₂。

Results of cAMP assay:

when tested in a cAMP assay, the compounds of the examples typically exhibit pA₂A value of greater than or equal to 6.5; preferably greater than or equal to 7.5; more preferably greater than or equal to 8.5. The following table describes the activity of the compounds of the examples tested. The activity ranges A, B and C refer to pA in the cAMP assay₂The values, as shown below: "A": pA is₂ 6.5≤x<7.5，“B”：pA₂ 7.5≤x<8.5，“C”：8.5≤pA₂。

Table 6 below shows the results in Ca²⁺And pIC of the compounds of the examples tested in cAMP assay₅₀And pA₂The value is obtained. pA is₂Or Ca²⁺A blank in the analysis column indicates that the corresponding compound has not been tested in the corresponding assay or that no results have been obtained.

Table 6:

B-IIC: oligo dendritic cell maturation/myelination assay

The effect of GPR17 negative regulators on primary oligodendrocyte maturation/myelination can be assessed in vitro by immunoassay methods using antibodies to Myelin Basic Protein (MBP) as a marker for mature oligodendrocytes.

Description of MBP Western blot (blot)/oligo-dendritic cell/myelination assay

After 3-4 days in proliferation medium, rat primary OPCs were seeded at a density of 25,000 cells per square centimeter in 12-well tissue culture plates and switched to growth factor-free neuronal medium to induce spontaneous in vitro differentiation and GPR17 protein expression. For final differentiation and quantitative analysis of protein expression, after 24-48 hours, growth factor-free medium was supplemented with 0.20ng/mL triiodothyronine (T3) and 10ng/mL ciliary neurotrophic factor (ciliary neurological factor) with 1 μ M GPR17 antagonist/inverse agonist test compound or vehicle for an additional 3 days. After compound treatment, cells were washed twice with ice cold PBS and lysed in ice cold lysis buffer (25mM Tris, pH 7.4, 150mM NaCl, 1mM EDTA, 1% Triton X-100, 1% IGEPAL) supplemented with a protease inhibitor cocktail. The lysate (lysate) was spun at 4 ℃ for 20 minutes and centrifuged at 15,000 Xg at 4 ℃ for 10 minutes. Protein concentrations were determined using the Pierce BCA protein assay according to the manufacturer's instructions. 7.5-15. mu.g of protein were separated by 10% SDS-polyacrylamide gel electrophoresis and transferred to a nitrocellulose membrane by electroblotting (electroblotting). After washing, the membranes were blocked (Block) with Roti-Block for 1 hour at room temperature and incubated with MBP antibody (1:5000, Life span BioSciences) in Roti-Block overnight at 4 ℃. The membranes were washed 3 times with PBS containing 0.1% Tween and then incubated with horseradish (horseradish) peroxidase-coupled goat anti-mouse IgG antibody for 1 hour at room temperature in Roti-Block. ECL Prime Using Amersham Biosciences

Western blot detection reagents immunoreactive proteins were visualized by chemiluminescence and quantified by densitometry using Gelscan software. For normalization (normalization) to equal loading and protein transfer, the membranes were probed again with an anti- β -actin antibody (1:2500, BioLegend; secondary antibody goat anti-rabbit IgG antibody hrp (abin)). The change in the amount of MBP expression in the presence of the test compound is compared to the MBP expression under control conditions.

The expression of myelin by addition of 1 μ M compound I-22 (6-chloro-N- [6- (difluoromethoxy) -5-fluoro-2-methoxypyridin-3-yl ] -1H-pyrrolo [2,3-b ] pyridine-3-sulfonamide) is shown in fig. 1 (N ═ 4, mean and SD).

Description of MBP fiber disc/oligodendrocyte maturation/myelination assay

The compounds of the invention can also be tested for activity in a fiber disc assay, as shown below:

16,000-22,000 OPC cells per square centimeter were seeded in a Mimetix aligned 96-well fiber disc (Electrospining). After 2 days in proliferation medium and 2 days in growth factor-free neuronal medium to induce spontaneous in vitro differentiation and GPR17 protein expression, vehicle or 1 μ M antagonist/inverse agonist test compound was added to the final differentiation medium supplemented with 0.20ng/mL triiodothyronine and 10ng/mL ciliary neurotrophic factor for 6 days, and the medium was changed after 3 days. The cells were then fixed in 4% paraformaldehyde (paraformaldehyde) followed by PBS wash, permeabilization in PBS with 0.1% TritonX-100 (permeabilization), and blocking with phosphate buffer with 10% goat serum and 1% bovine serum albumin (blocking). MBP antibody will be diluted in blocking buffer (1: 2000) and incubated at 37 ℃ for 1 hour. The cells were washed again in PBS and incubated for 1 hour with a secondary antibody (Millipore, 1: 500) coupled to Cy2 directed against mouse IgG. After PBS wash, cells were stained with 0.2. mu.g/mL DAPI, washed again and fixed with Mowiol. Fluorescence images were taken using a Zeiss AxioObserver. Z1 microscope equipped with an ApoTome imaging system and a Plan-Apochromat 20X/0.8 objective, an eGFP filter (excitation 470/40 nm; emission 525/50nm) and a DAPI filter (excitation 365 nm; emission 445/50 nm). At least 15 random areas of control (final differentiation medium with 0.1% DMSO) and test compounds were imaged using the same setup treated with Zeiss ZEN2.3 software. Changes in the number of myelin fibres can be reported by a set of fibre lengths (0 to 40 μm, 41 to 60 μm, 61 to 80, 81 to 100, 101 to 120 and >120 μm) in the absence or presence of the GPR17 negative modulator disclosed herein.

Claims

1. A compound of the formula I,

wherein

X1 is N or C (R7),

r2 and R4 are independently selected from hydrogen or fluorine,

r5 is hydrogen or a halogen,

R6 together with R7 and the C atom to which they are attached form a five-or six-membered aromatic or non-aromatic ring, which may include one or two ring-forming heteroatoms, wherein the ring is unsubstituted or substituted by one to three residues R13,

r7, if present, is selected from hydrogen, halogen, cyclopropyl, cyclopropyloxy, C_1-3Alkoxy, and C_1-3Alkyl, wherein each alkyl and alkoxy may be substituted by one or more groups selected from halogen, C_1-2Alkoxy, fluoro (C)_1-2) Alkoxy and cyano, or as described above, R7 and R6 together form a ring,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

r13 is independently at each occurrence selected from the group consisting of halogen, hydroxy, cyano, methyl, methoxy, fluoromethyl and fluoromethoxy,

2. The compound of claim 1, wherein

X1 is N or C (R7),

r2 is hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

R6 together with R7 and the C atom to which they are attached form a pyridine ring, such that the pyridine group forms with its bicyclic ring system a 1H-pyrrolo [3,2-H ] quinoline, wherein the pyridine ring is substituted or preferably unsubstituted by one or two residues R13,

R7 and R6 together form a ring, as described above,

r10 is selected from hydrogen, cyano, halogen, C_3-5Cycloalkyl radical, C_3-5Cycloalkyl oxy, C_3-5Cycloalkyl methoxy, C_1-4Alkoxy, and C_1-4Alkyl, wherein each cycloalkyl, cycloalkyloxy, alkyl and alkoxy may be mono-or poly-substitutedPlural is selected from halogen, C_1-3Alkoxy, fluoro (C)_1-3) Alkoxy and cyano, and a substituent group of the cyano,

r11 is selected from hydrogen, fluoro and methoxy,

x2 is N or C (R12),

r12 is selected from hydrogen, methoxy and halogen,

3. A compound according to any one of the preceding claims wherein R2, R4 and R5 are all hydrogen and R6 is selected from halogen, cyano, fluoromethoxy and fluoromethyl.

4. A compound according to any preceding claim, wherein R8 is selected from fluoro and methoxy.

5. A compound according to any one of the preceding claims, wherein R10 is selected from halogen, cyclopropyl and C_1-2Alkoxy, wherein the alkoxy may optionally be substituted by one or more substituents selected from the group consisting of fluoro, methoxy, ethoxy and fluoro C_1-2Substituent of alkoxy.

6. A compound according to any preceding claim, wherein R10 is selected from halogen, methoxy, ethoxy, fluoromethoxy, fluoroethoxy and fluoromethoxyethoxy.

7. A compound according to any preceding claim, wherein R11 is hydrogen or fluoro, preferably fluoro.

8. A compound according to any preceding claim, wherein

R2, R4 and R5 are all hydrogen,

x1 is N or C (R7),

r7, if present, is selected from hydrogen and fluorine,

r8 is selected from the group consisting of fluoro and methoxy,

r10 is selected from the group consisting of chlorine, bromine, cyclopropyl and C_1-2Alkoxy, wherein the alkoxy is substituted with up to three fluorine atoms or with a substituent selected from the group consisting of methoxy, fluoromethoxy and fluoroethoxy,

r11 is hydrogen or fluorine,

x2 is N or C (R12),

r12, if present, is hydrogen or fluorine, preferably hydrogen,

9. A compound according to any one of claims 1 to 8, wherein X2 is N, having the formula II wherein all substituents are as described in the preceding claims, and pharmaceutically acceptable salts, solvates, isotopes and co-crystals thereof

10. The compound of claim 9, wherein

X1 is N or C (R7),

r2, R4 and R5 are all hydrogen,

r6 is chloro or fluoromethyl,

r8 is selected from the group consisting of fluoro and methoxy,

r11 is a fluorine atom or a fluorine atom,

x2 is N or C (R12),

and R12, if present, is hydrogen.

11. The compound of any one of claims 1 to 8, wherein X2 is-C (R12) -, thus having formula III

Wherein all substituents are as defined in claims 1 to 8, and pharmaceutically acceptable salts, solvates, isotopes and co-crystals thereof.

12. The compound of claim 11, wherein

R2, R4 and R5 are all hydrogen,

r6 is selected from halogen, cyano, methyl, isopropyl, methoxy, fluoromethoxy, fluoromethyl and benzyloxy,

x1 is N or C (R7),

r7, if present, is selected from hydrogen, halogen, fluoromethoxy and fluoromethyl,

r11 is selected from hydrogen, methoxy and fluoro,

r12 is selected from the group consisting of hydrogen and fluorine,

13. The compound of any one of claims 1 to 8, wherein X1 is-C (R7) -, thus having formula IV,

14. The compound of claim 13, wherein

R2, R4 and R5 are all hydrogen,

r7 is selected from hydrogen, halogen, fluoromethoxy and fluoromethyl,

x2 is N or C (R12),

r11 is selected from hydrogen, methoxy and fluoro,

r12, if present, is selected from hydrogen, methoxy and fluoro,

15. A compound according to any one of claims 1 to 8, wherein X1 is N, thus having formula V

16. The compound of claim 15, wherein

R2, R4 and R5 are all hydrogen,

r6 is halogen, cyano, methyl, isopropyl, methoxy, fluoromethoxy, fluoromethyl and benzyloxy,

x2 is N or C (R12),

r12, if present, is selected from hydrogen, methoxy and fluoro.

17. The compound of claim 1, having formula VI:

wherein

n is 0 to 3, preferably 0 or 1,

x3 is a CH or N,

r2 is hydrogen or fluorine,

r4 is hydrogen or fluorine,

r5 is hydrogen or a halogen,

x2 is N or C (R12),

r11 is selected from hydrogen, fluoro and methoxy,

r12 is selected from hydrogen, methoxy and halogen,

18. The compound of claim 17, wherein

n is a number of 0, and n is,

x3 is N or CH,

r2 and R4 are both hydrogen,

r5 is hydrogen or halogen, preferably hydrogen,

r8 is selected from hydrogen, fluoro and methoxy,

r11 is hydrogen or fluorine,

x2 is N or C (R12), and

r12, if present, is selected from hydrogen, methoxy and fluoro,

19. A compound selected from

6-chloro-N- (6-cyclopropyl-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (5-chloro-3-methoxypyrazin-2-yl) -1H-indole-3-sulfonamide,

n- (5-bromo-3-methoxypyrazin-2-yl) -6-chloro-1H-indole-3-sulfonamide,

6-chloro-N- (2, 5-difluoro-6-methylpyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (5-fluoro-2, 6-dimethoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (2, 5-difluoro-6-methoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-5-fluoro-2-methoxypyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-2, 5-difluoropyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-iodopyridin-3-yl) -1H-indole-3-sulfonamide,

6-chloro-N- (6-chloro-4-fluoropyridin-3-yl) -1H-indole-3-sulfonamide,

20. A compound according to any preceding claim for use in therapy.

21. A compound as claimed in any preceding claim for use in the treatment or prevention of demyelinating disorders (demyelination disorders), including but not limited to multiple sclerosis.

22. A method of treatment or prophylaxis of a demyelinating disorder, including but not limited to multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in any preceding claim.

23. A therapeutic composition comprising a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier.