Cystic fibrosis membrane conductance regulatory factor modulator

Abstract

The present disclosure provides cystic fibrosis transmembrane conductance regulator (CFTR) modulators, pharmaceutical compositions comprising at least one such modulator, methods of treating cystic fibrosis using such modulators and pharmaceutical compositions, and processes for making such modulators.

Description

[Technical Field]

[0001] This application claims the benefits of U.S. Provisional Application No. 63 / 063,194, filed on 7 August 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present invention relates to a cystic fibrosis membrane conductance regulator (CFTR) modulator, a pharmaceutical composition comprising the modulator, a method for treating cystic fibrosis and CFTR-mediated disorders using the modulator and the pharmaceutical composition, and a process for producing such modulator.

[0003] Cystic fibrosis (CF) is a recessive genetic disorder that affects approximately 83,000 children and adults worldwide. Despite advances in treatment, there is no cure for CF.

[0004] In patients with cystic fibrosis (CF), mutations in the CFTR gene, intrinsically expressed in the respiratory epithelium, lead to decreased apical anion secretion and imbalances in ion and fluid transport. The resulting decrease in anion transport contributes to increased mucus accumulation in the lungs, ultimately leading to microbial infections that can be fatal to CF patients. In addition to respiratory illness, CF patients typically suffer from gastrointestinal disorders and pancreatic insufficiency that, if left untreated, can be fatal. Furthermore, the majority of men with cystic fibrosis are infertile, and women with cystic fibrosis experience reduced fertilization rates.

[0005] Sequence analysis of the CFTR gene has revealed various disease-causing mutations (Cutting, G et al. (1990) Nature 346:366-369, Dean, M. et al. (1990) Cell 61:863:870, and Kerem, BS. et al. (1989) Science 245:1073-1080, Kerem, BS et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, more than 2,000 mutations have been identified in the CF gene, and currently the CFTR2 database contains information on only 322 of these identified mutations, with sufficient evidence to define 281 mutations as disease-causing. The most common disease-causing mutation is the deletion of phenylalanine at position 508 of the CFTR amino acid sequence, commonly referred to as the F508del mutation. This mutation occurs in many cases of cystic fibrosis and is associated with severe disease.

[0006] CFTR is a cAMP / ATP-mediated anion channel expressed in various cell types, including absorptive and secretory epithelial cells, where CFTR regulates transmembrane anion flux and modulates the activity of other ion channels and proteins. In epithelial cells, normal CFTR function is essential for maintaining systemic electrolyte transport, including in respiratory and digestive tissues. CFTR is composed of 1480 amino acids encoding a protein consisting of tandem repeats of transmembrane domains, each containing six transmembrane helices and a nucleotide-binding domain. Two transmembrane domains are linked to multiple phosphorylation sites that control channel activity and cell transport via a large polarity regulatory (R) domain.

[0007] Chloride transport involves the coordinated activity of ENaC (epithelial sodium channel) and CFTR located on the apical membrane, and Na expressed on the basolateral surface of cells. + -K + -ATPase pump and Cl -It is caused by coordinated activity with the channel. Secondary active transport of chloride from the lumen side results in the accumulation of intracellular chloride, which then passively leaves the cell via the Cl - channel and can result in vectorial transport. The Na + / 2Cl - / K + cotransporter, the Na + -K + -ATPase pump and the basolateral membrane K + channel, as well as the placement of CFTR on the luminal side, regulate chloride secretion. Since probably water itself is not actively transported, its flow across the epithelium depends on a small transepithelial osmotic gradient created by large fluxes of sodium and chloride.

[0008] More recently, several CFTR modulators have been identified. These modulators are considered, for example, as potentiators, corrector agents, potentiator boosters / co-potentiators, amplifiers, read-through agents, and nucleic acid therapies. CFTR modulators that increase the channel gating activity of mutant and wild-type CFTR at the epithelial cell surface are known as potentiators. Corrector agents improve defective protein processing and result in transport to the epithelial surface. Ghelani and Schneider-Futschik (2020) ACS Pharmacol. Transl. Sci. 3:4-10. There are three CFTR corrector agents approved by the US Food and Drug Administration for the treatment of cystic fibrosis. However, monotherapy with some CFTR corrector agents has been found to be not sufficiently effective, and as a result, combination therapy with a potentiator is required to enhance CFTR activity. Currently, there is only one CFTR potentiator approved for the treatment of cystic fibrosis. Therefore, although the treatment of cystic fibrosis is being transformed by these new small molecule CFTR modulators, new and better modulators are needed to prevent disease progression, reduce the severity of cystic fibrosis and other CFTR-mediated diseases, and treat more severe forms of these diseases. SUMMARY OF THE INVENTION [Means for solving the problem]

[0009] One aspect of the present invention provides compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, novel compounds comprising compounds 1 to 53 and compounds 54 to 77, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the foregoing.

[0010] For example, the compound of formula I is [ka] , It can also be shown as its deuterated derivative and pharmaceutically acceptable salt, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these can independently be hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), C3-C8 cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases combine to form a ring selected from C3-C8 cycloalkyl and 3-6 membered heterocyclyl, or one exists on one atom and the other on an adjacent atom R YThese two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2)2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, where ring C is C6-C 10 Selected from aryls and 5-10 membered heteroaryls, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, 7, and 8. m is selected from 0, 1, 2, and 3.

[0011] In some embodiments, X is -O-.

[0012] In some embodiments, R YEach of these can independently be hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), C3-C8 cycloalkyl, and -OR Y1 Selected from, in the formula, Q and R Y1 It is defined above. In some embodiments, -OR Y1 It is -OH.

[0013] In some embodiments, Q is optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups, C3-C8 cycloalkyl and C6-C 10 Selected from the aryl group. In some embodiments, Q is independently selected from each of the following: [ka] Selected from.

[0014] In some embodiments, R Y Each is independent of the others. Hydrogen, fluorine, [ka] Selected from.

[0015] In some embodiments, ring B is selected from C3-C8 cycloalkyl and phenyl groups, which are optionally substituted with 1 to 3 groups independently selected from halogens. In some embodiments, ring B is [ka] Selected from.

[0016] In some embodiments, n is selected from 4, 5, and 6.

[0017] In some embodiments, -(Y) n -teeth, [ka] [ka] It is a base selected from among them.

[0018] In some embodiments, R 1 Each of these is independently a C1-C6 alkyl group (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), -N(R 2 )2, and -CO2R 2 Selected from, in the formula, R 2 R is defined above. In some embodiments, 1 Each of these is independently selected from -CF3, -NH2, -NH(CH2CH3), CO2H, and CH2OH.

[0019] In some embodiments, R 2 Each of these is independently selected from hydrogen and C1-C6 alkyl groups.

[0020] In some embodiments, Z is [ka] Selected from, in the formula, R Z1 , R Z2 , and ring C is as defined above. In some embodiments, Z is [ka] And in the formula, R Z1 and R Z2 It is defined above. In some embodiments, Z is [ka] And in the formula, R Z1 and R Z2 It is defined above. In some embodiments, Z is [ka] And in the formula, RZ1 and R Z2 It is defined above. In some embodiments, Z is [ka] And in the formula, R Z1 and R Z2 (R) is as defined above, where (R) refers to the stereochemical designation of the central carbon atom according to the Kahn-Ingold Prelogue Agreement. In some embodiments, Z is [ka] And in the formula, R Z1 and R Z2 (S) is as defined above, and (S) refers to the stereochemical designation of the central carbon atom under the Kahn-Ingold Prelogue Agreement.

[0021] In some embodiments, [ka] teeth, [ka] Selected from.

[0022] In some embodiments, [ka] teeth, [ka] Selected from.

[0023] In some embodiments, R Z1 R is selected from hydrogen and C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from halogens). In some embodiments, R Z1 R is selected from hydrogen and -CF3. In some embodiments, R Z1 It is -CF3.

[0024] In some embodiments, R Z2 It is hydroxyl.

[0025] In some embodiments, Z is [ka] Selected from. In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] That is the case.

[0026] In some embodiments, m is selected from 1 and 2.

[0027] In some embodiments, the compound of the present invention is of formula I' [ka] , It is also encompassed by its deuterated derivatives and pharmaceutically acceptable salts, X is -O-, Y is independent of each other, -C(R Y )2-, -O-, and [ka] Selected from, R YEach of these is independently selected from hydrogen and C1-C6 alkyl (which are optionally substituted with 1 to 3 groups independently selected from hydroxyl and Q), Ring B is selected from C3-C8 cycloalkyl groups, Q is optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups, C3-C8 cycloalkyl and C6-C 10 Selected from the alphabet, R 1 Each of these is independently selected from C1-C6 alkyl (which is optionally substituted with 1 to 6 groups independently of the halogen) and -NH2, Z [ka] And, R Z1 However, it is selected from C1-C6 alkyl groups (which are optionally substituted with 1 to 6 groups independently of the halogen), R Z2 However, it is hydroxyl, n is selected from 5 and 6. m is 2.

[0028] In some embodiments, Q in equation I' is independent of each other. [ka] Selected from.

[0029] In some embodiments, R of formula I' Y Each is independent of the others. hydrogen, [ka] Selected from.

[0030] In some embodiments, the ring B of formula I' is, [ka] That is the case.

[0031] In some embodiments, the -(Y) of formula I' n -teeth, [ka] It is a base selected from among them.

[0032] In some embodiments, R of formula I' Z1 It is -CF3.

[0033] In some embodiments, Z in formula I' is [ka] In some embodiments, Z in formula I' is [ka] That is the case.

[0034] In some embodiments, n in formula I' is 5. In some embodiments, n in formula I' is 6.

[0035] In some embodiments, the compound of the present invention is of formula I” [ka] , It is also encompassed by its deuterated derivatives and pharmaceutically acceptable salts, In the formula, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10Aryl, 5- to 10-membered heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - selected from, or two instances of R Y on the same atom combine to form a ring selected from C 3- C8 cycloalkyl and 3- to 6-membered heterocyclyl, or one is on one atom and the other is on an adjacent atom, and two instances of R Y combine to form a π bond, R Y are each independently hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy and Q), C6-C 10 aryl, 5- to 10-membered heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - selected from, or one is on one atom and the second is on an adjacent atom, and two instances of R Y combine to form a π bond, R Y1 are each independently selected from hydrogen and C1-C6 alkyl, or two instances of R Y1 bonded to the same nitrogen combine to form a 3- to 6-membered heterocyclyl, Ring B is ■ C6-C 10 aryl (optionally substituted with 1 to 3 groups independently selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy), ■ C3-C8 cycloalkyl, ■ 5- to 10-membered heteroaryl, and ■ 3- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl) selected from, Q is each independently ■ C1-C6 alkyl, where 〇 halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, RZ2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, and 7. m is selected from 0, 1, 2, and 3.

[0036] In some embodiments, X in formula I' is -O-.

[0037] In some embodiments, Y in formula I'' is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined in equation I''.

[0038] In some embodiments, Y in formula I'' is -C(R Y )2-, and in the formula, R Y This is defined in equation I''.

[0039] In some embodiments, R of formula I'' Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, R Y1 And Q are as defined in Equation I''.

[0040] In some embodiments, R of formula I'' Y Each is independent of the others. hydrogen, [ka] Selected from, In the formula, Q is defined as in formula I''.

[0041] In some embodiments, Q in formula I'' is independent of each other. ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0042] In some embodiments, Q in formula I'' is independent of each other. [ka] Selected from.

[0043] In some embodiments, the ring B of formula I'' is optionally replaced with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0044] In some embodiments, the ring B of formula I'' is [ka] Selected from.

[0045] In some embodiments, the -(Y) of formula I'' n -teeth, [ka] It is a base selected from among them.

[0046] In some embodiments, R of formula I'' 1 These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 ) Selected from 2, in the formula, R 2R is defined in formula I''. In some embodiments, R of formula I'' 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in equation I''.

[0047] In some embodiments, R of formula I'' 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 3 groups independently selected from halogens). In some embodiments, R of formula I'' 2 Each is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, R of formula I'' 2 Each of them is hydrogen.

[0048] In some embodiments, Z in formula I'' is [ka] And in the formula, R Z1 and R Z2 is defined in formula I''. In some embodiments, Z in formula I'' is [ka] And in the formula, R Z1 and R Z2 This is defined in formula I. In some embodiments, Z in formula I is [ka] That is the case.

[0049] In some embodiments, R of formula I'' Z1 R is selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens). In some embodiments, R of formula I'' Z1It is -CF3.

[0050] In some embodiments, R of formula I'' Z2 It is hydroxyl.

[0051] In some embodiments, n in formulas I, I', and / or I'' is selected from 4, 5, and 6. In some embodiments, n in formulas I, I', and / or I'' is 5. In some embodiments, n in formulas I, I', and / or I'' is 6.

[0052] In some embodiments, m in formulas I, I', and / or I'' is selected from 1 and 2. In some embodiments, m in formulas I, I', and / or I'' is 1. In some embodiments, m in formulas I, I', and / or I'' is 2.

[0053] Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, and any of the aforementioned deuterated derivatives, and at least one pharmaceutically acceptable carrier, which may further comprise at least one additional active pharmaceutical ingredient. Accordingly, another aspect of the present invention provides a method for treating cystic fibrosis, a CFTR-mediated disease, comprising administering to a subject in need of such treatment at least one pharmaceutically acceptable carrier as part of a pharmaceutical composition comprising a compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, and any of the aforementioned deuterated derivatives, and optionally at least one additional ingredient.

[0054] In certain embodiments, the pharmaceutical composition of the present invention comprises compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, the compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, and A composition comprising compounds of formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof may optionally further comprise at least one compound selected from compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0055] Another aspect of the present invention is a method for treating CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need at least one compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, and a deuterated derivative of any of the foregoing, and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methyl (Tylpropan-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide (Compound II), N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound III), or N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinolin N-3-carboxamide (compound III-d), 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid (compound IV), N-(1,3-dimethylpyrazole-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl] [pyridine-3-carboxamide (compound V), N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound VI), (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole-1-yl]-12,12-dimethyl-2λ 6-Thi-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaen-2,2,4-trione (compound VII), (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexane-5-yl}-9-oxa-2λ 6 The present invention provides a method comprising further administration of one or more additional CFTR modifiers optionally selected from -thia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaen-2,2,13-trione (compound VIII), N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound IX), and N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxy-phenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound X).

[0056] Another aspect of the present invention is a method for treating CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need at least one compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, and any of the aforementioned deuterated derivatives, [ka] (ASP-11) (disclosed in Journal of Cystic Fibrosis (2018), 17(5), 595-606), and [ka] The present invention provides a method comprising further administration of one or more additional CFTR modifiers selected from (nesolicaftor or PTI-428) (disclosed in WO2016 / 105485). In one embodiment, the additional CFTR modifier is ASP-11. In one embodiment, the additional CFTR modifier is PTI-428.

[0057] Another aspect of the present invention is a method for treating CFTR-mediated disease cystic fibrosis, comprising administering to a patient in need at least one compound selected from the novel compounds disclosed herein, a pharmaceutically acceptable salt thereof, and any of the aforementioned deuterated derivatives, [ka] (galicaftor or ABBV-2222) (disclosed in U.S. Patent Application Publication No. 2016-0120841), [ka] (ABBV-3221) (Disclosed in WO2018 / 065921), [ka] The present invention provides a method comprising further administration of one or more additional CFTR modifiers selected from (posenacaftor or PTI-801) (disclosed in WO2017 / 062581), ABBV-2851 (disclosed in WO2017 / 009804), GLPG2737 (disclosed in U.S. Patent Application Publication No. 2017-0101405), ABBV-3748, ABBV-3903, and ABBV-119, in an optional manner.

[0058] Another aspect of the present invention provides formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, for use in any of the methods described herein. [Brief explanation of the drawing]

[0059] [Figure 1] This provides the X-ray power diffraction (XRPD) pattern of compound 11heptane solvate. [Figure 2] This provides overlays of X-ray power diffraction (XRPD) patterns of compound 11-heptane solvates prepared under three different drying conditions. [Figure 3] This provides DSC analysis of compound 11heptane solvate. [Figure 4] This provides the 13C solid-state NMR spectrum of compound 11heptane solvate. [Figure 5] This provides the 19F solid-state NMR spectrum of compound 11heptane solvate. [Figure 6A] This provides the thermogravimetric analysis (TGA) curve for compound 11 heptane solvate (drying conditions 1). [Figure 6B] This provides the thermogravimetric analysis (TGA) curve for compound 11 heptane solvate (drying conditions 2). [Figure 6C] This provides the thermogravimetric analysis (TGA) curve for compound 11heptane solvate (drying conditions 3). [Modes for carrying out the invention]

[0060] definition As used herein, "Compound II" refers to (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide, which can be represented by the following structure. [ka] Compound II may be in the form of a pharmaceutically acceptable salt. Compound II, as well as methods for preparing and using Compound II, are disclosed in WO2010 / 053471, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, and WO2015 / 160787, which are incorporated herein by reference, respectively.

[0061] As used throughout this disclosure, "Compound III" refers to N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide, which is represented by the following structure. [ka] Compound III may also be in the form of a pharmaceutically acceptable salt. Compound III, as well as methods for preparing and using Compound III, are disclosed in WO2006 / 002421, WO2007 / 079139, WO2010 / 108162, and WO2010 / 019239, respectively, which are incorporated herein by reference.

[0062] In some embodiments, a deuterated derivative of compound III (compound III-d) is used in the compositions and methods disclosed herein. The chemical name of compound III-d is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide, which is represented by the following structure. [ka] Compound III-d may be in the form of a pharmaceutically acceptable salt. Compound III-d, as well as methods for preparing and using Compound III-d, are disclosed in WO2012 / 158885, WO2014 / 078842, and U.S. Patent No. 8,865,902, which are incorporated herein by reference.

[0063] As used herein, "Compound IV" refers to 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid, which is represented by the following chemical structure. [ka] Compound IV may be in the form of a pharmaceutically acceptable salt. Compound IV, as well as methods for preparing and using Compound IV, are disclosed in WO2007 / 056341, WO2009 / 073757, and WO2009 / 076142, which are incorporated herein by reference.

[0064] As used herein, "compound V" refers to N-(1,3-dimethylpyrazole-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure. [ka] Compound V may be in the form of a pharmaceutically acceptable salt. Compound V, as well as methods for preparing and using Compound V, are disclosed in WO2018 / 107100 and WO2019 / 113476, which are incorporated herein by reference.

[0065] As used herein, "Compound VI" refers to N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure. [ka] Compound VI may be in the form of a pharmaceutically acceptable salt. Compound VI, as well as methods for preparing and using Compound VI, are disclosed in WO2018 / 064632, which is incorporated herein by reference.

[0066] As used herein, "compound VII" refers to (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole-1-yl]-12,12-dimethyl-2λ 6 -Thi-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, represented by the following chemical structure. [ka] Compound VII may be in the form of a pharmaceutically acceptable salt. Compound VII, as well as methods for preparing and using Compound VII, are disclosed in WO2019 / 152940 and U.S. Provisional Patent Application No. 62 / 886,660, which are incorporated herein by reference.

[0067] As used herein, "Compound VIII" refers to (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2.3]hexane-5-yl}-9-oxa-2λ 6 -Tia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione, which is represented by the following chemical structure. [ka] Compound VIII may be in the form of a pharmaceutically acceptable salt. Compound VIII, as well as methods for preparing and using Compound VIII, are disclosed in PCT / US2020 / 026331, which is incorporated herein by reference.

[0068] As used herein, "compound IX" refers to N-(benzenesulfonyl)-6-(3-fluoro-5-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure. [ka] Compound IX may be in the form of a pharmaceutically acceptable salt. Compound IX, as well as methods for preparing and using Compound IX, are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0069] As used herein, "compound X" refers to N-[(6-amino-2-pyridyl)sulfonyl]-6-(3-fluoro-5-isobutoxyphenyl)-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide, which is represented by the following chemical structure. [ka] Compound X may be in the form of a pharmaceutically acceptable salt. Compound X, as well as methods for preparing and using Compound X, are disclosed in WO2016 / 057572, which is incorporated herein by reference.

[0070] As used herein, the term "alkyl" refers to saturated branched or unbranched aliphatic hydrocarbons having carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms). Alkyl groups may be substituted or unsubstituted.

[0071] As used herein, the term "π bond" refers to a covalent bond formed by the p orbitals of adjacent atoms. π bonds exist when there are multiple bonds, i.e., double or triple bonds, between two atoms. For example, a carbon-carbon double bond consists of one π bond, and a carbon-carbon triple bond consists of two π bonds.

[0072] As used herein, the term "haloalkyl" refers to an alkyl or alkyl group substituted with one or more halogen atoms.

[0073] As used herein, the term "alkoxy" refers to an alkyl or cycloalkyl group covalently bonded to an oxygen atom. The alkoxy group may be substituted or unsubstituted.

[0074] As used herein, the term "haloalkoxyl group" refers to an alkoxy group substituted with one or more halogen atoms.

[0075] As used herein, “cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 carbon atoms (e.g., 3 to 10 carbon atoms). “Cycloalkyl” groups include monocyclic, bicyclic, tricyclic, crosslinked, condensed, and spiro rings, including monospiro rings and dispiro rings. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and dispiro[2.0.2.1]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0076] As used herein, the term “heteroaryl ring” refers to an aromatic ring containing at least one ring atom that is a heteroatom such as O, N, or S.

[0077] As used herein, the terms “heterocyclyl ring” and “heterocyclyl” refer to non-aromatic hydrocarbons having 3 to 12 atoms (e.g., 3 to 10 atoms) in the ring, including at least one ring atom that is a heteroatom such as O, N, S, or Si. A “heterocyclyl” ring encompasses monocyclic, bicyclic, tricyclic, polycyclic, bridging, condensed, and spiro rings, including monospiro rings and dispiro rings.

[0078] "Substitutable" means that at least one hydrogen of the "substituted" group is replaced by a substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each of its substituted positions, and the substituents may be the same or different at each position if more than one position in any given structure can be substituted by more than one substituent selected from the specified group.

[0079] Examples of nitrogen protecting groups include, for example, t-butyl carbamate (Boc), benzyl carbamate (Bn), para-methoxybenzyl carbamate (PMB), tetrahydropyranyl carbamate (THP), carbamin 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), methyl carbamate, ethyl carbamate, 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), allyl carbamate (Aloc or Alloc), formamide, acetamide, benzamide, allylamine, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. A comprehensive list of nitrogen protecting groups can be found in Wuts, PGM, “Greene's Protective Groups in Organic Synthesis: Fifth Edition,” 2014, John Wiley and Sons.

[0080] As used herein, “deuterated derivatives” means the same chemical structure in which one or more hydrogen atoms are replaced by deuterium atoms. In some embodiments, deuterated derivatives are compounds in which one or more hydrogen atoms of an alkyl group are replaced by deuterium atoms.

[0081] As used herein, "CFTR" means cystic fibrosis membrane conductance regulator.

[0082] As used herein, the term "CFTR modulator" refers to a compound that increases the activity of CFTR. The increase in activity brought about by a CFTR modulator includes, but is not limited to, compounds that correct, enhance, stabilize, and / or amplify CFTR.

[0083] As used herein, the term "CFTR corrector" refers to a compound that promotes the processing and transport of CFTR, thereby increasing the amount of CFTR on the cell surface.

[0084] As used herein, the term "CFTR enhancer" refers to a compound that enhances ion transport by increasing the channel activity of CFTR proteins located on the cell surface. The novel compounds disclosed herein are CFTR enhancers.

[0085] As used herein, the terms “CFTR enhancer,” “CFTR enhancer,” and “CFTR co-enhancer” are interchangeable and refer to compounds that enhance CFTR enhancement.

[0086] As used herein, the terms “active pharmaceutical ingredient” (“API”) or “therapeutic agent” refer to a biologically active compound.

[0087] As used herein, the term "one or more additional therapeutic agents" includes the possibility that only one therapeutic agent may be present.

[0088] The terms "patient" and "subject" are used interchangeably and refer to animals, including humans.

[0089] The terms “effective dose” and “effective amount” are used interchangeably herein and refer to the amount of compound administered that produces the desired effect (e.g., improvement of CF or symptoms of CF, or reduction of the severity of CF or symptoms of CF). The exact amount of the effective dose will vary depending on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0090] As used herein, terms such as “treatment” and “to treat” generally mean improvement of one or more symptoms of CF in the subject, or reduction of the severity of CF or one or more symptoms of CF. As used herein, “treatment” includes, but is not limited to, increased growth, increased weight gain, reduction of mucous membranes in the lungs, improvement of pancreatic and / or hepatic function, reduction of lung infections, and / or reduction of cough or shortness of breath in the subject. Improvement of any of these symptoms or reduction of their severity can be readily assessed according to standard methods and techniques known in the art.

[0091] As used herein, the term "in combination with" means that, when referring to two or more compounds, drugs, or additional active pharmaceutical ingredients, the two or more compounds, drugs, or active pharmaceutical ingredients are administered to the patient before or after each other, or simultaneously with each other.

[0092] The terms “about” and “approximately,” when used in relation to the dose, volume, or weight percentage of an ingredient in a composition or dosage form, include a specified dose, volume, or weight percentage value, or a range of doses, volumes, or weight percentages recognized by those skilled in the art to provide an equivalent pharmacological effect to that obtained from a specified dose, volume, or weight percentage. The terms “about” and “approximately” may also refer to an acceptable error to a particular value determined by those skilled in the art, which depends in part on how that value is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. As used herein, the symbol “~” appearing immediately before a number has the same meaning as the terms “about” and “approximately.”

[0093] As used herein, the term “solvent” refers to any liquid in which the product is at least partially soluble (solubility of the product greater than 1 g / L).

[0094] As used herein, the terms "room temperature" or "ambient temperature" mean a temperature between 15°C and 30°C.

[0095] It should be understood that certain compounds of the present invention may exist as separate stereoisomers or enantiomers, and / or as mixtures of such stereoisomers or enantiomers. When used in the chemical structures disclosed herein, the "wedge" to the stereoatom [ka] or "hash" [ka] The bond represents a chiral center of known absolute stereochemistry (i.e., one stereoisomer). When used in the chemical structures disclosed herein, it represents a "wavy" bond to a stereoatom. [ka] This represents a chiral center of unknown absolute stereochemistry (i.e., one stereoisomer). When used in the chemical structures disclosed herein, it represents a "wavy" bond to the double bond carbon. [ka] This indicates a mixture of E / Z isomers. When used in the chemical structures disclosed herein, it refers to the stereoforming atoms. [ka] A (linear) bond indicates the presence of a mixture (e.g., a racemic compound or concentrate). As used herein, two carbon atoms of a double bond [ka] The term "linear" indicates that the double bond has an E / Z stereochemistry. When used in the chemical structures disclosed herein, [ka] The (wavy line perpendicular to the linear bond to group "A") indicates that group "A" is a substituent and that its bond point is the end of a bond terminated by a wavy line. Where used herein, stereoatoms denoted by (R) or (S) indicate the stereochemical designation of the stereoatom according to the Kahn-Ingold Prelogue Agreement.

[0096] Certain compounds disclosed herein may exist as tautomers even if only a single tautomer structure is shown, and both tautomer forms are intended. For example, a description of compound A is understood to include its tautomer compound B, and vice versa, and is also considered to include mixtures thereof. [ka]

[0097] As used herein, “minimal function (MF) mutations” refer to CFTR gene mutations associated with minimal CFTR function (CFTR proteins that are little to no function), and these mutations include, for example, mutations associated with severe deficiencies in the ability of CFTR channels to open and close, known as channel gating deficiencies or “gating mutations,” mutations associated with severe deficiencies in CFTR cellular processing and its delivery to the cell surface, mutations associated with no or minimal CFTR synthesis, and mutations associated with severe deficiencies in channel conductance.

[0098] As used herein, the term “pharmaceutically acceptable salt” refers to a salt form of the compound of the Disclosure in which the salt is nontoxic. pharmaceutically acceptable salts of the compounds of the Disclosure include those derived from suitable inorganic and organic acids and bases. The “free base” form of the compound does not include, for example, ionic salts.

[0099] The phrase "and their pharmaceutically acceptable salts and deuterated derivatives" is used interchangeably with "and their pharmaceutically acceptable salts and any of the aforementioned deuterated derivatives" with respect to one or more compounds or formulas of the present invention. These phrases are intended to encompass a pharmaceutically acceptable salt of any one of the reference compounds, a deuterated derivative of any one of the reference compounds, and pharmaceutically acceptable salts of those deuterated derivatives.

[0100] Those skilled in the art will recognize that when an amount of "a compound or a pharmaceutically acceptable salt thereof" is disclosed, the amount of the pharmaceutically acceptable salt form of the compound corresponds to the concentration of the free base of the compound. Note that the amounts of compounds or pharmaceutically acceptable salts disclosed herein are based on their free base forms.

[0101] Suitable pharmaceutically acceptable salts are disclosed, for example, in SMBerge, et al. J. Pharmaceutical Sciences, 1977, 66, 1-19. For example, Table 1 of that paper provides the following pharmaceutically acceptable salts. [Table 1]

[0102] Non-limiting examples of pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, or perchloric acid; salts formed with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; and salts formed using other methods used in the art, such as ion exchange. Non-limiting examples of pharmaceutically acceptable salts include adipines, alginates, ascorbic acid, aspartates, benzenesulfons, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfons, citrates, cyclopentanepropionates, diglucons, dodecyl sulfates, ethanesulfons, formates, fumarates, glucoheptons, glycerophosphates, glucons, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy- Examples include ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, and valersates. Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4This includes alkyl) 4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Preferred non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. Other preferred non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0103] As used herein, the term “amorphous” refers to a solid material that does not have long-range order in the position of its molecules. An amorphous solid is a generally supercooled liquid in which molecules are randomly arranged, such that there is no clearly defined arrangement, e.g., no molecular packing and no long-range order. Amorphous solids are generally isotropic, that is, they exhibit similar properties in all directions and do not have a distinct melting point. For example, an amorphous material is a solid material that does not have sharp, characteristic crystalline peaks in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or more broad peaks (e.g., halos) are observed in its XRPD pattern. Broad peaks are characteristic of amorphous solids. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. In some embodiments, the solid material may contain amorphous compounds, for example, the solid material may be characterized by the absence of sharp, characteristic crystalline peaks in its XRPD spectrum (i.e., the solid material is not crystalline but amorphous as determined by XRPD). Instead, one or more broad peaks (e.g., halos) may be observed in the XRPD pattern of the solid material. For a comparison of XRPDs of amorphous and crystalline materials, see US2004 / 0006237. Solid materials containing amorphous compounds may be characterized, for example, by a glass transition temperature lower than the melting point of a pure crystalline solid. Other techniques, such as solid-state NMR, can also be used to characterize the crystalline or amorphous form.

[0104] As used herein, the terms “crystalline form” and “form” are interchangeable to refer to a crystalline structure (or polymorph) having a specific molecular packing arrangement within the crystal lattice. Crystalline forms are determined, for example, by X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, and 13 C solid-state nuclear magnetic resonance ( 13 They can be identified and distinguished from one another by one or more characterization techniques, including C SSNMR. Therefore, as used herein, the term “crystalline form of compound I [X]” means, for example, XRPD, single-crystal X-ray diffraction, and 13This refers to a unique crystalline morphology that can be identified and distinguished from other morphologies by one or more characterization techniques, including C SSNMR. In some embodiments, the novel crystalline morphology is characterized by an X-ray powder diffractogram having one or more signals at one or more identified two-theta values ​​(°2θ).

[0105] As used herein, the term “free form” refers to the non-ionized version of a compound in its solid state. Examples of free forms include free bases and free acids.

[0106] As used herein, the term “solvate” refers to a crystalline form comprising one or more molecules of the compound herein, wherein one or more molecules of a solvent (possibly stoichiometric or nonstoichiometric) are incorporated into the crystal lattice. When the solvent is water, the solvate is referred to as a “hydrate.”

[0107] In some embodiments, the solid material may comprise a mixture of crystalline and amorphous solids. A solid material comprising an amorphous compound may, for example, comprise up to 30% crystalline solid. In some embodiments, a solid material prepared to comprise an amorphous compound may also comprise, for example, up to 25%, 20%, 15%, 10%, 5%, or 2% crystalline solid. In embodiments in which the solid material comprises a mixture of crystalline and amorphous solids, characterization data such as XRPD may include indices for both crystalline and amorphous solids. In some embodiments, the crystalline form of the disclosure may comprise up to 30% amorphous compound. In some embodiments, a crystalline preparation of the compound of formula I may comprise up to 25%, 20%, 15%, 10%, 5%, or 2% amorphous solid.

[0108] As used herein, the term “substantially amorphous” refers to a solid material that has little or no long-range order at the molecular positions. For example, a substantially amorphous material has a degree of crystallinity of less than 15% (e.g., less than 10%, or less than 5%, or less than 2%). Note that the term “substantially amorphous” also includes the descriptive term “amorphous,” which refers to a material that has no degree of crystallinity (0%).

[0109] As used herein, the term “substantially crystalline” refers to a solid material that contains little to no amorphous molecules. For example, a substantially crystalline material has less than 15% amorphous molecules (e.g., less than 10%, less than 5%, or less than 2%). Note that the term “substantially crystalline” also includes the descriptive term “crystalline,” which refers to a material that is 100% crystalline.

[0110] As used herein, a crystalline form is "substantially pure" if it accounts for 90% by weight or more of the total amount of all solid forms in a sample, as determined by methods in accordance with the art, such as quantitative XRPD. In some embodiments, a solid form is "substantially pure" if it accounts for 95% by weight or more of the total amount of all solid forms in a sample. In some embodiments, a solid form is "substantially pure" if it accounts for 99% by weight or more of the total amount of all solid forms in a sample. Note that the term "substantially pure" also includes the descriptive term "pure," which refers to a substance that is 100% pure.

[0111] As used herein, the term "XRPD" refers to an analytical characterization method of X-ray powder diffraction. The XRPD patterns disclosed herein are recorded in transmission or reflection configuration using a diffractometer under ambient conditions.

[0112] As used herein, the term “ambient conditions” means room temperature, ambient conditions, and uncontrolled humidity conditions. The terms “room temperature” and “ambient temperature” mean 15°C to 30°C.

[0113] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern,” and “XRPD spectrum” are interchangeable to refer to experimentally obtained patterns plotting signal locations (on the x-axis) against signal intensity (on the y-axis). For amorphous materials, an X-ray powder diffractogram may contain one or more broad signals; for crystalline materials, an X-ray powder diffractogram may contain one or more signals, each identified by its angular value measured at 2θ (°2θ) shown on the x-axis of the X-ray powder diffractogram, which may be expressed as “the signal at 2θ of ...,” “the signal at the 2θ value of [a] of ...,” and / or “the signal at at least the 2θ value of ... selected from ....”

[0114] As used herein, “signal” or “peak” refers to a point in an XRPD pattern where the intensity measured by counting is maximum. Those skilled in the art will recognize that one or more signals (or peaks) in an XRPD pattern may overlap and, for example, may not be apparent to the naked eye. In fact, those skilled in the art will recognize that several methods recognized in the art, such as the Rietveld method, can and are suitable for determining whether a signal is present in a pattern.

[0115] As used herein, "signal at 2 degrees theta" refers to the X-ray reflection position measured and observed in an X-ray powder diffraction experiment (°2θ).

[0116] The repeatability of the measured angle values ​​is within the range of ±0.2°2θ, meaning that the angle value can be the enumerated angle value +0.2°2theta, the angle value -0.2°2theta, or any value between the two endpoints (between angle value +0.2°2theta and angle value -0.2°2theta).

[0117] The terms "signal intensity" and "peak intensity" are interchangeable in referring to the relative signal intensity within a given X-ray powder diffractogram. Factors that may affect the relative signal intensity or peak intensity include the thickness of the sample and the preferred orientation (e.g., crystalline particles are not randomly distributed).

[0118] As used herein, an X-ray powder diffractogram is considered "substantially similar to that in a particular figure" if at least 90% of the signals in two diffractograms overlap, for example, at least 95%, at least 98%, or at least 99%. In determining "substantially similar," a person skilled in the art will understand that variations in intensity and / or signal position can exist in XRPD diffractograms even for the same crystalline form. Therefore, a person skilled in the art will understand that the maximum signal value (at degree 2θ) in an XRPD diffractogram is generally identified as ±0.2 degrees 2θ of the reported value, which is the dispersion recognized in the art.

[0119] As used herein, solid-state nuclear magnetic resonance (SSNMR) spectra are considered "substantially similar to those in [a particular] figure" if at least 90% of the signals in two spectra overlap, e.g., at least 95%, at least 98%, or at least 99%. In determining "substantially similar," a person skilled in the art will understand that variations in intensity and / or signal position can exist in SSNMR spectra even for the same crystalline form. Accordingly, a person skilled in the art will understand that a chemical shift in an SSNMR spectrum (parts per million (ppm) as referred herein) generally means that the value is specified as ±0.2 ppm of the reported value, which is a dispersion recognized in the art.

[0120] As used herein, the term "X-ray powder diffractogram having a signal at 2-theta values" refers to an XRPD pattern that includes the X-ray reflection position (°2θ) measured and observed in an X-ray powder diffraction experiment.

[0121] As used herein, the term "DSC" refers to the differential scanning calorimetry analytical method.

[0122] As used herein, the term “decomposition start” refers to the intersection of the baseline before the transition and the mutual reflection tangent.

[0123] As used herein, the term “glass transition temperature” or “Tg” refers to the temperature at which a “glassy” amorphous solid, which is hard and brittle above, becomes viscous or rubbery.

[0124] As used herein, the term "TGA" refers to the thermogravimetric (or thermogravimetric) analysis method. Detailed description of the embodiment

[0125] In addition to compounds of formulas I, I', and I'', pharmaceutically acceptable salts thereof, and deuterated derivatives of these compounds and salts, the present invention provides compounds of formulas I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1 to 53, compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0126] For example, in some embodiments, the compound of formula I is the compound of formula Ia. [ka] , Furthermore, selected from its deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these independently consists of hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, and 7.

[0127] In some embodiments, X in equation Ia is -O-.

[0128] In some embodiments, Y in equation Ia is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined as shown in equation Ia.

[0129] In some embodiments, Y in formula Ia is -C(R Y )2-, and in the formula, R Y This is defined in equation Ia.

[0130] In some embodiments, R of formula Ia Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in equation Ia.

[0131] In some embodiments, R of formula Ia Y Each is independent of the others. hydrogen, [ka] Selected from.

[0132] In some embodiments, Q in equation Ia is independent of each other. ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0133] In some embodiments, Q in equation Ia is independent of each other. [ka] Selected from.

[0134] In some embodiments, the ring B of formula Ia is optionally substituted with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0135] In some embodiments, the ring B of formula Ia is [ka] Selected from.

[0136] In some embodiments, -(Y) of formula Ia n -teeth, [ka] It is a base selected from among them.

[0137] In some embodiments, R of formula Ia 1 These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 )2, and in the formula, R 2 This is defined in formula Ia. In some embodiments, R of formula Ia 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in equation Ia.

[0138] In some embodiments, R of formula Ia2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 3 groups independently selected from the halogen). In some embodiments, R of formula Ia 2 Each is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, R of formula Ia 2 Each of them is hydrogen.

[0139] In some embodiments, Z in formula Ia is, [ka] And in the formula, R Z1 and R Z2 This is defined in equation Ia.

[0140] In some embodiments, R of formula Ia Z1 C 1-C6 Selected from alkyl groups (optionally substituted with 1 to 3 groups selected from halogens). In some embodiments, R of formula Ia Z1 It is -CF3.

[0141] In some embodiments, R of formula Ia Z2 It is hydroxyl.

[0142] In some embodiments, n in formula Ia is selected from 4, 5, and 6. In some embodiments, n in formula Ia is 6.

[0143] In some embodiments, the compound of formula I is the compound of formula IIa, formula IIb, and formula IIc. [ka] Furthermore, selected from their deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. m is selected from 0, 1, 2, and 3.

[0144] In some embodiments, m in formula IIa, IIb, or IIc is selected from 1 and 2. In some embodiments, m in formula IIa, IIb, or IIc is 2.

[0145] In some embodiments, the compound of formula I is the compound of formula IId, formula IIe, and formula IIf, [ka] Furthermore, selected from their deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom YThese two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2)2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3- to 6-membered heterocycline.

[0146] In some embodiments, X, -O- are of formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0147] In some embodiments, Y in formula IIa, IIb, IIc, IId, IIe, or IIf is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0148] In some embodiments, Y in formulas IIa, IIb, IIc, IId, IIe, or IIf is -C(R Y )2-, and in the formula, R Y This is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0149] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0150] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf Y Each is independent of the others. hydrogen, [ka] Selected from, In the formulas, Q is defined as in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0151] In some embodiments, Q in formulas IIa, IIb, IIc, IId, IIe, or IIf is independent of each other. ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0152] In some embodiments, Q in formulas IIa, IIb, IIc, IId, IIe, or IIf is independent of each other. [ka] Selected from.

[0153] In some embodiments, ring B of formula IIa, IIb, IIc, IId, IIe, or IIf is optionally replaced with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0154] In some embodiments, the ring B of formula IIa, formula IIb, formula IIc, formula IId, formula IIe, or formula IIf is [ka] Selected from.

[0155] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf 1 These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 )2, and in the formula, R 2 R is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf. In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf is used. 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0156] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 3 groups independently selected from the halogen). In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf. 2 Each is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, R of formula IIa, formula IIb, formula IIc, formula IId, formula IIe, or formula IIf 2 Each of them is hydrogen.

[0157] In some embodiments, Z in formulas IIa, IIb, IIc, IId, IIe, or IIf is [ka] And in the formula, R Z1 and R Z2 This is defined in formulas IIa, IIb, IIc, IId, IIe, or IIf.

[0158] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf Z1 R is selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens). In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf Z1 It is -CF3.

[0159] In some embodiments, R of formulas IIa, IIb, IIc, IId, IIe, or IIf Z2 It is hydroxyl.

[0160] In some embodiments, the compound of formula I is formula IIIa, formula IIIb, and formula IIIc. [ka] During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. m is selected from 0, 1, 2, and 3.

[0161] In some embodiments, m in formula IIIa, formula IIIb, or formula IIIc is selected from 1 and 2. In some embodiments, m in formula IIIa, formula IIIb, and formula IIIc is 2.

[0162] In some embodiments, the compound of formula I is the compound of formula IIId, formula IIIe, and formula IIIf, [ka] Furthermore, selected from their deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R YEach of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10Selected from the aryl, or R Z3 These two cases combine to form a 3- to 6-membered heterocycline.

[0163] In some embodiments, X in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is -O-.

[0164] In some embodiments, Y in formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined by equations IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0165] In some embodiments, Y in formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is -C(R Y )2-, and in the formula, R Y This is defined in equations IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0166] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in equations IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0167] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf Y Each is independent of the others. hydrogen, [ka] Selected from, In the formulas, Q is defined as in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0168] In some embodiments, Q in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently: ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0169] In some embodiments, Q in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is independently: [ka] Selected from.

[0170] In some embodiments, ring B of formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is optionally replaced with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0171] In some embodiments, the ring B of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf is [ka] Selected from.

[0172] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf 1These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 )2, and in the formula, R 2 R is defined in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf. In some embodiments, R of formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is used. 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in equations IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0173] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups that are optionally substituted with 1 to 3 groups independently selected from the halogen). In some embodiments, R of formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf. 2 Each of these is independently selected from hydrogen and C1-C6 alkyl groups.

[0174] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf 2 Each of them is hydrogen.

[0175] In some embodiments, Z in formulas IIIa, IIIb, IIIc, IIId, IIIe, or IIIf is [ka] Thus, Z is defined in equations IIIa, IIIb, IIIc, IIId, IIIe, or IIIf.

[0176] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf Z1 R is selected from C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from halogens). In some embodiments, R of formula IIIa, IIIb, IIIc, IIId, IIIe, or IIIf Z1 It is -CF3.

[0177] In some embodiments, R of formula IIIa, formula IIIb, formula IIIc, formula IIId, formula IIIe, or formula IIIf Z2 It is hydroxyl.

[0178] In some embodiments, the compound of formula I is the compound of formula I'''. [ka] , Furthermore, selected from its deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these can independently be hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), C3-C8 cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom YThese two cases combine to form a ring selected from C3-C8 cycloalkyl and 3-6 membered heterocyclyl, or one exists on one atom and the other on an adjacent atom R Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2)2, -CN, phenyl, benzyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, n is selected from 4, 5, 6, 7, and 8. m is selected from 0, 1, 2, and 3.

[0179] In some embodiments, X in formula I''' is -O-.

[0180] In some embodiments, R of formula I''' Y Each of these can independently be hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), C3-C8 cycloalkyl, and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in formula I'''. In some embodiments, the -OR of formula I''' is used. Y1 It is -OH.

[0181] In some embodiments, Q in formula I''' is optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups, C3-C8 cycloalkyl and C6-C 10 Selected from the aryl group. In some embodiments, Q in formula I''' is independently, [ka] Selected from.

[0182] In some embodiments, R of formula I''' Y Each is independent of the others. Hydrogen, fluorine, [ka] Selected from.

[0183] In some embodiments, ring B of formula I''' is selected from C3-C8 cycloalkyl and phenyl groups, which are optionally substituted with 1 to 3 groups independently selected from halogens. In some embodiments, ring B of formula I''' is [ka] Selected from.

[0184] In some embodiments, n in formula I''' is selected from 4, 5, and 6.

[0185] In some embodiments, the -(Y) of formula I''' n -teeth, [ka] [ka] It is a base selected from among them.

[0186] In some embodiments, R of formula I'''1 Each of these is independently a C1-C6 alkyl group (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), -N(R 2 )2, and -CO2R 2 Selected from, in the formula, R 2 is defined in formula I'''. In some embodiments, R of formula I''' 1 Each of these is independently selected from -CF3, -NH2, -NH(CH2CH3), CO2H, and CH2OH.

[0187] In some embodiments, R of formula I''' 2 Each of these is independently selected from hydrogen and C1-C6 alkyl groups.

[0188] In some embodiments, R of formula I''' Z1 R is selected from hydrogen and C1-C6 alkyl (optionally substituted with 1 to 6 groups selected from halogens). In some embodiments, R of formula I''' Z1 It is -CF3.

[0189] In some embodiments, R of formula I''' Z2 It is hydroxyl.

[0190] In some embodiments, R of formula I''' Z1 The R of formula I''' is a C1-C6 alkyl group (optionally substituted with 1 to 6 groups selected from halogens), and Z2 is hydroxyl. In some embodiments, R of formula I''' Z1 is -CF3, and R of equation I''' Z2 It is hydroxyl.

[0191] In some embodiments, m in formula I''' is selected from 1 and 2.

[0192] In some embodiments, the compound of formula I is the compound of formula IIa'. [ka] , Furthermore, selected from its deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, m is selected from 0, 1, 2, and 3.

[0193] In some embodiments, m in formula IIa' is selected from 1 and 2. In some embodiments, m in formula IIa' is 2.

[0194] In some embodiments, X in formula IIa' is -O-.

[0195] In some embodiments, Y in formula IIa' is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined as shown in equation IIa'.

[0196] In some embodiments, Y in formula IIa' is -C(R Y )2-, and in the formula, R Y This is defined in equation IIa'.

[0197] In some embodiments, R of formula IIa' Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in equation IIa'.

[0198] In some embodiments, R of formula IIa' Y Each is independent of the others. hydrogen, [ka] Selected from, In the equation, Q is defined as shown in equation IIa'.

[0199] In some embodiments, Q in equation IIa' is independently, ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0200] In some embodiments, Q in equation IIa' is independently, [ka] Selected from.

[0201] In some embodiments, ring B of formula IIa' is optionally substituted with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0202] In some embodiments, ring B of formula IIa' is, [ka] Selected from.

[0203] In some embodiments, R of formula IIa' 1 These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 )2, and in the formula, R 2 This is defined in formula IIa'. In some embodiments, R in formula IIa' 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in equation IIa'.

[0204] In some embodiments, R of formula IIa' 2Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 3 groups independently selected from the halogen). In some embodiments, R of formula IIa' 2 Each is independently selected from hydrogen and C1-C6 alkyl. In some embodiments, R of formula IIa' 2 Each of them is hydrogen.

[0205] In some embodiments, R of formula IIa' Z1 C 1-C6 Selected from alkyl groups (optionally substituted with 1 to 6 groups selected from halogens). In some embodiments, R of formula IIa' Z1 It is -CF3.

[0206] In some embodiments, R of formula IIa' Z2 It is hydroxyl.

[0207] In some embodiments, R of formula IIa' Z1 The R in formula IIa' is a C1-C6 alkyl group (optionally substituted with 1 to 6 groups selected from halogens), and Z2 is hydroxyl. In some embodiments, R of formula IIa' Z1 is -CF3, and R in equation IIa' Z2 It is hydroxyl.

[0208] In some embodiments, the compound of formula I is the compound of formula IIIa'. [ka] , Furthermore, selected from its deuterated derivatives and pharmaceutically acceptable salts, During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y)2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, m is selected from 0, 1, 2, and 3.

[0209] In some embodiments, X in equation IIIa' is -O-.

[0210] In some embodiments, Y in equation IIIa' is independently -C(R Y )2-, -CO-, and [ka] Selected from, in the formula, R Y And ring B is defined as shown in equation IIIa'.

[0211] In some embodiments, Y in formula IIIa' is -C(R Y )2-, and in the formula, R Y This is defined in equation IIIa'.

[0212] In some embodiments, R of formula IIIa' Y Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 Selected from, in the formula, Q and R Y1 This is defined in equation IIIa'.

[0213] In some embodiments, R of formula IIIa' Y Each is independent of the others. hydrogen, [ka] Selected from, In the equation, Q is defined as shown in equation IIIa'.

[0214] In some embodiments, Q in equation IIIa' is independent of each other. ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 Selected from the arrows.

[0215] In some embodiments, Q in equation IIIa' is independent of each other. [ka] Selected from.

[0216] In some embodiments, ring B of formula IIIa' is optionally substituted with 1 to 3 groups independently selected from the halogen, C6-C 10 Selected from the arrows.

[0217] In some embodiments, ring B of formula IIIa' is [ka] Selected from.

[0218] In some embodiments, R of formula IIIa' 1 These are independently C1-C6 alkyl (which can be optionally substituted with 1 to 3 groups independently of the halogen) and -N(R 2 )2, and in the formula, R 2 R is defined in formula IIIa'. In some embodiments, R of formula IIIa' 1 These are independently -CF3 and -N(R 2 ) Selected from 2, in the formula, R 2 This is defined in equation IIIa'.

[0219] In some embodiments, R of formula IIIa' 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 3 groups independently selected from halogens). In some embodiments, R of formula IIIa' 2 Each of these is independently selected from hydrogen and C1-C6 alkyl groups.

[0220] In some embodiments, R of formula IIIa'2 Each of them is hydrogen.

[0221] In some embodiments, R of formula IIIa' Z1 C 1-C6 Selected from alkyl groups (optionally substituted with 1 to 6 groups selected from halogens). In some embodiments, R of formula IIIa' Z1 It is -CF3.

[0222] In some embodiments, R of formula IIIa' Z2 It is hydroxyl.

[0223] In some embodiments, R of formula IIIa' Z1 The R in formula IIIa' is a C1-C6 alkyl group (optionally substituted with 1 to 6 groups selected from halogens), and Z2 is hydroxyl. In some embodiments, R of formula IIIa' Z1 is -CF3, and R in equation IIIa' Z2 It is hydroxyl.

[0224] The compounds of the present invention include compounds 1 to 53 and compounds 54 to 77, as well as their deuterated derivatives and pharmaceutically acceptable salts. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0225] Treatment method The novel compounds disclosed herein, such as those of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, and their pharmaceutically acceptable salts, as well as deuterated derivatives of such compounds and salts, can all act as CFTR modulators, i.e., regulate CFTR activity in the body. Individuals suffering from mutations in the gene encoding CFTR may benefit from accepting CFTR modulators. CFTR mutations affect CFTR levels, i.e., CFTR channels on the cell surface. Mutations can affect the number of CFTR channels or their function, i.e., the functional ability of each channel to open and transport ions. Mutations that affect CFTR quantity include mutations that cause synthesis defects (Class I defects), mutations that cause processing and transport defects (Class II defects), mutations that cause decreased CFTR synthesis (Class V defects), and mutations that reduce CFTR surface stability (Class VI defects). Mutations that affect CFTR function include mutations that cause gating defects (Class III defects) and mutations that cause conductance defects (Class IV defects). Some CFTR mutations exhibit characteristics of multiple classes. Certain mutations in the CFTR gene lead to the development of cystic fibrosis.

[0226] Accordingly, in some embodiments, the present invention relates to a method for treating cystic fibrosis in a patient, a method for reducing its severity, or a method for treating it symptomatically, comprising to the patient an effective amount of the novel compounds disclosed herein, for example, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, pharmaceutically acceptable salts thereof, and / or deuteration of such compounds and salts. The present invention provides a method comprising administering one of the derivatives alone or in combination with another active ingredient, such as another CFTR modulator. In some embodiments, the patient has the F508del / minimal function (MF) genotype, the F508del / F508del genotype (homozygous for the F508del mutation), the F508del / gating genotype, or the F508del / residual function (RF) genotype. In some embodiments, the patient is heterozygous and has one F508del mutation. In some embodiments, the patient is homozygous for the N1303K mutation.

[0227] In some embodiments, 1 mg to 1000 mg of the compounds disclosed herein, pharmaceutically acceptable salts thereof, or deuterated derivatives of such compounds or salts are administered daily.

[0228] In some embodiments, the patient is heterozygous, having the F508del mutation in one allele and a mutation selected from Table 2 in the other allele. [Table 3-1] [Table 3-2]

[0229] In some embodiments, the disclosure also covers methods of treatment using isotopically labeled compounds of the aforementioned compounds or pharmaceutically acceptable salts thereof, the formulas and variables of such compounds and salts being as described above or as described in any other embodiments described above, provided that one or more atoms therein are replaced (isotopically labeled) by atoms having an atomic mass or mass number different from that of atoms normally found in nature. Examples of commercially available isotopes suitable for the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is one example.

[0230] Isotope-labeled compounds and salts can be used in several beneficial ways. They may be suitable for various types of assays, such as drug and / or substrate tissue distribution assays. For example, tritium ( 3 H) Labeling and / or carbon-14 ( 14 C) Labeled compounds are particularly useful in various types of assays, such as substrate tissue distribution assays, due to their relatively simple preparation and excellent detection ability. For example, deuterium ( 2 H) Labeled compounds are therapeutically useful, non 2 It has superior therapeutic potential advantages compared to H-labeled compounds. Generally speaking, deuterium ( 2H) Labeled compounds and salts may have higher metabolic stability compared to unlabeled compounds due to the kinetic isotope effect described below. Higher metabolic stability directly translates to a desired increase in in vivo half-life or lower dosage. Isotopically labeled compounds and salts can typically be prepared by following the procedures disclosed in the Synthesis Schemes and Related Descriptions, Examples, and Preparations sections of this specification, and by replacing unisotopically labeled reactants with readily available isotopely labeled reactants.

[0231] In some embodiments, the isotope-labeled compound and salt are deuterium ( 2 H) Labeled compounds and salts. In some specific embodiments, the isotope-labeled compounds and salts are deuterium ( 2 H) Labeled compounds and salts in which one or more hydrogen atoms are replaced by deuterium. In the chemical structure, deuterium is, 2 It is represented by "H" or "D".

[0232] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It may be reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism.

[0233] deuterium( 2 H) Labeled compounds and salts can modulate the oxidative metabolism of compounds by primary kinetic isotope effects. Primary kinetic isotope effects are changes in the rate of chemical reactions resulting from the exchange of isotopic nuclei, which are then caused by changes in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of heavier isotopes usually results in a decrease in the ground state energy of the chemical bond, and therefore a decrease in rate-determining bond breakdown. If bond breakdown occurs within or near the saddle point region along the coordination of a multi-product reaction, the product distribution ratio can change significantly. For illustrative purposes, if deuterium is bonded to a carbon atom in an inexchangeable position, k M / k DA typical rate difference is between 2 and 7. For further consideration, see SL.Harbeson and RDTung, Deuterium In Drug Discovery and Development, Ann.Rep.Med.Rep.Med.Chem. 2011, 46, 403-417, which is incorporated herein by reference.

[0234] The concentration of the isotope (e.g., deuterium) incorporated into the isotope-labeled compounds and salts of this disclosure may be defined by the isotope enrichment factor. As used herein, the term “isotope enrichment factor” means the ratio between the isotopic abundance and the natural abundance of a given isotope. In some embodiments, when the substituents of the compounds of the present disclosure are represented by deuterium, such compounds have an isotopic enrichment factor for each of the specified deuterium atoms of at least 3500 (52.5% deuterium incorporation for each of the specified deuterium atoms), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0235] Combination therapy One embodiment disclosed herein provides a method for treating cystic fibrosis and other CFTR-mediated diseases by using any of the novel compounds disclosed herein, such as compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds 1 to 53, compounds 54 to 77, pharmaceutically acceptable salts thereof, and deuterated derivatives of such compounds and salts, in combination with at least one additional active pharmaceutical ingredient.

[0236] Accordingly, in some embodiments, the present invention provides a method for treating cystic fibrosis in a patient, a method for reducing its severity, or a method for treating it symptomatically, comprising administering to the patient an effective amount of any of the novel compounds disclosed herein, for example, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, pharmaceutically acceptable salts thereof, and / or deuterated derivatives of such compounds and salts, either alone or in combination with at least one additional active pharmaceutical ingredient, such as a CFTR modifier.

[0237] In some embodiments, at least one additional active pharmaceutical ingredient is selected from mucolytics, bronchodilators, antibiotics, anti-infectives, and anti-inflammatorys.

[0238] In some embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhalation powder (TIP); azithromycin; aztreonam, including an aerosolized form of aztreonam; amikacin, including a liposomal formulation of amikacin; ciprofloxacin, including a formulation of ciprofloxacin suitable for administration by inhalation; levoflaxacin, including an aerosolized formulation of levoflaxacin; and a combination of two antibiotics, for example, fosfomycin and tobramycin.

[0239] In some embodiments, additional agents are mucolytics. An exemplary mucolytic useful herein is Pulmozyme®.

[0240] In some embodiments, additional agents are bronchodilators. Exemplary bronchodilators include albuterol, metaproterenol sulfate, pyrbuterol acetate, salmeterol, or tetrabrine sulfate.

[0241] In some embodiments, additional agents are anti-inflammatory agents, i.e., agents that can reduce inflammation in the lungs. Examples of such agents useful herein include ibuprofen, docosahexaenoic acid (DHA), sildenafil, inhaled glutathione, pioglitazone, hydroxychloroquine, or simavastatin.

[0242] In some embodiments, the additional agent is a nutritional supplement. Exemplary nutritional supplements include Pancrease®, Pancreacarb®, Ultrase®, or Creon®, Liprotomasase® (formerly Trizytek®), Aquadeks®, or pancrelipase (pancreatic enzyme substitution) including glutathione inhalation. In one embodiment, the additional nutritional supplement is pancrelipase.

[0243] In some embodiments, at least one additional active pharmaceutical ingredient is selected from CFTR modifiers. In some embodiments, the CFTR modifier is a CFTR corrector. In some embodiments, the CFTR modifier is a CFTR enhancer / co-enhancer (e.g., ASP-11). In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR amplifier. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR readthrough agent. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy.

[0244] In some embodiments, at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist.

[0245] In some embodiments, at least one additional active pharmaceutical ingredient is selected from (a) Compound II and its pharmaceutically acceptable salts and deuterated derivatives, (b) Compound IV and its pharmaceutically acceptable salts and deuterated derivatives, (c) Compound V and its pharmaceutically acceptable salts and deuterated derivatives, (d) Compound VI and its pharmaceutically acceptable salts and deuterated derivatives, (e) Compound VII and its pharmaceutically acceptable salts and deuterated derivatives, and (f) Compound VIII and its pharmaceutically acceptable salts and deuterated derivatives. Accordingly, in some embodiments, the combination therapy provided herein comprises compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof. In some embodiments, the combination therapy provided herein comprises, (a) Compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) At least one compound selected from compound II and compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof; (c) At least one compound selected from compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof.In some embodiments, the combination therapies provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound II, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (c) at least one compound selected from compound VII, and pharmaceutically acceptable salts and deuterated derivatives thereof.

[0246] In some embodiments, the combination therapy provided herein comprises (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) compound II, The present invention comprises at least one compound selected from Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, and Compound X, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from the compounds disclosed in (c)WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, or Journal of Cystic Fibrosis (2018), 17(5), 595-606.

[0247] In some embodiments, the combination therapy provided herein comprises (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) compound II, compound (c) comprising at least one compound selected from IV, compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801.

[0248] In some embodiments, the combination therapy provided herein comprises (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) WO2019 / 195739, WO2019 / 200246, WO2021 / 030555, WO2021 / 030556, WO2017 / 173274, WO2019 / 010092, WO2019 / 018353, WO2010 / 053471 , WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, WO2015 / 160787, WO2007 / 056341, WO200 9 / 073757, WO2009 / 076142, WO2018 / 107100, WO2019 / 113476, WO2018 / 064632, WO2019 / 15294 0, WO2016 / 057572, WO2021 / 030554, WO2020 / 206080, WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Journal of Cystic Fibrosis(2018),17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3, or Son,J.-Includes at least two compounds selected from those disclosed in H. et al., Eur. J. of Med. Chem. 2020, 112888.

[0249] In some embodiments, the combination therapy provided herein comprises (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, ( b) comprising at least two compounds selected from Compound II, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801, as well as pharmaceutically acceptable salts and deuterated derivatives thereof.

[0250] In some embodiments, the combination therapy provided herein comprises (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b ) Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2 851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, ARN 23765, ARN23766, PTI-801, FDL-176, PTI-808(dirocaftor), GLPG1837, GLPG2451 / ABBV-2451, QBW251(icenticaftor) r), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9 (c) comprising at least one compound selected from 411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and (c) at least one pharmaceutically acceptable carrier.

[0251] In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound II, and their pharmaceutically acceptable salts and deuterated derivatives. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound IV, and their pharmaceutically acceptable salts and deuterated derivatives. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound V, and their pharmaceutically acceptable salts and deuterated derivatives. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound VI, and their pharmaceutically acceptable salts and deuterated derivatives.In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound VII, and their pharmaceutically acceptable salts and deuterated derivatives. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives are administered in combination with at least one compound selected from compound VIII, and their pharmaceutically acceptable salts and deuterated derivatives.

[0252] Compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, 54-77, compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and their pharmaceutically acceptable salts and deuterated derivatives are each independently administered once daily. It can be administered twice or three times a day. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered once a day. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered twice daily. In some embodiments, compounds of formulas I, I', I'', I' Compounds of formulas Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and their pharmaceutically acceptable salts and deuterated derivatives, and at least one compound selected from compound II, and their pharmaceutically acceptable salts and deuterated derivatives, are administered once daily.In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound II, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered once daily. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound IV, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound V, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered once daily.In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound V, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VI, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered once daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VI, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VII, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered once daily.In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VII, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VIII, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered once daily. In some embodiments, compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compound VIII, and pharmaceutically acceptable salts and deuterated derivatives thereof, are administered twice daily.

[0253] In some embodiments, a compound of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, at least one compound selected from compounds II and IV, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one compound selected from compounds V, VI, VII, VIII, IX, and X, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered once daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered twice daily. In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, at least one compound selected from compound II and a pharmaceutically acceptable salt thereof, and at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof are administered once daily.In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, at least one compound selected from compound II and a pharmaceutically acceptable salt thereof, and at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof are administered twice daily.

[0254] Compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and their pharmaceutically acceptable salts and deuterated derivatives may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions. Such pharmaceutical compositions may be administered once daily or multiple times daily, for example, twice daily. As used herein, the phrase "a given amount of API (e.g., compound II, compound VII, or their pharmaceutically acceptable salts) administered once daily or twice daily" means that the given amount is administered per dose, and this dose may occur once or twice daily.

[0255] In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered in a first pharmaceutical composition, and at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof is administered in a second pharmaceutical composition.

[0256] In some embodiments, compounds of formula I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof are administered in a first pharmaceutical composition; at least one compound selected from compound II and a pharmaceutically acceptable salt thereof is administered in a second pharmaceutical composition; and at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof is administered in a third pharmaceutical composition.

[0257] Any suitable pharmaceutical composition known in the art is a compound of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds 1-53, compounds 54-77, compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, and any pharmaceutically acceptable compounds thereof. It can be used in salts and deuterated derivatives. Several exemplary pharmaceutical compositions of compound II and its pharmaceutically acceptable salts can be found in WO2011 / 119984 and WO2014 / 014841, which are incorporated herein by reference. Several exemplary pharmaceutical compositions of compound III and its pharmaceutically acceptable salts can be found in WO2007 / 134279, WO2010 / 019239, WO2011 / 019413, WO2012 / 027731, and WO Several exemplary pharmaceutical compositions of compound III-d and its pharmaceutically acceptable salts can be found in 2013 / 130669, and can be found in US8,865,902, US9,181,192, US9,512,079, WO2017 / 053455, and WO2018 / 080591, all of which are incorporated herein by reference. Several exemplary pharmaceutical compositions of compound IV and its pharmaceutically acceptable salts are incorporated herein by reference. Compound V can be found in WO2010 / 037066, WO2011 / 127421, and WO2014 / 071122. Several exemplary pharmaceutical compositions of compound V and its pharmaceutically acceptable salts can be found in WO2019 / 152940, which is incorporated herein by reference. Several exemplary pharmaceutical compositions of compound VI and its pharmaceutically acceptable salts can be found in WO2019 / 079760, which is incorporated herein by reference.

[0258] Pharmaceutical composition Another aspect of the present invention provides a pharmaceutical composition comprising compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least one pharmaceutically acceptable carrier.

[0259] In some embodiments, the present invention provides pharmaceutical compositions comprising compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, at least one compound selected from compounds 1-53 and 54-77, and pharmaceutically acceptable salts and deuterated derivatives thereof, in combination with at least one additional active pharmaceutical component. In some embodiments, the at least one additional active pharmaceutical component is a CFTR modulator. In some embodiments, the at least one additional active pharmaceutical component is a CFTR corrector. In some embodiments, the at least one additional active pharmaceutical component is a CFTR enhancer. In some embodiments, the at least one additional active pharmaceutical component is a compound that enhances CFTR enhancement, i.e., a CFTR enhancer enhancer / co-enhancer. In some embodiments, the at least one additional active pharmaceutical component is a CFTR amplification It is a drug. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR read-through agent. In some embodiments, at least one additional active pharmaceutical ingredient is a CFTR nucleic acid therapy. In some embodiments, at least one additional active pharmaceutical ingredient is an ENaC inhibitor. In some embodiments, at least one additional active pharmaceutical ingredient is a TMEM16A modulator. In some embodiments, at least one additional active pharmaceutical ingredient is a GPR39 agonist. In some embodiments, the present pharmaceutical composition provides a pharmaceutical composition comprising compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least two additional active pharmaceutical ingredients, each being a CFTR corrector.In some embodiments, the present pharmaceutical composition provides a pharmaceutical composition comprising compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and at least two additional active pharmaceutical components, one of which is a CFTR corrector and the other is a CFTR enhancer.

[0260] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound II, compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and a pharmaceutically acceptable salt thereof; and (c) at least one pharmaceutically acceptable carrier.

[0261] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound II and a pharmaceutically acceptable salt thereof; and (c) at least one pharmaceutically acceptable carrier.

[0262] In some embodiments, the present invention provides a pharmaceutical composition comprising (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof; and (c) at least one pharmaceutically acceptable carrier.

[0263] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound II and compound IV, and pharmaceutically acceptable salts thereof; (c) at least one compound selected from compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and pharmaceutically acceptable salts thereof; and (d) at least one pharmaceutically acceptable carrier.

[0264] In some embodiments, the present disclosure provides a pharmaceutical composition comprising (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, at least one compound selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; (b) at least one compound selected from compound II and a pharmaceutically acceptable salt thereof; (c) at least one compound selected from compound VII and a pharmaceutically acceptable salt thereof; and (d) at least one pharmaceutically acceptable carrier.

[0265] In some embodiments, the pharmaceutical compositions provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) compound II , at least one compound selected from compound IV, compound V, compound VI, compound VII, compound VIII, compound IX, and compound X, and pharmaceutically acceptable salts and deuterated derivatives thereof, (c) WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Journal of Cystic Fibrosis(2018),17(5),595-606,Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669,Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640,Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One (d) comprising at least one compound selected from the compounds disclosed in 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.2019,10,3, or Son,J.-H.et al.,Eur.J.ofMed.Chem.2020,112888, and (d) at least one pharmaceutically acceptable carrier.

[0266] In some embodiments, the pharmaceutical compositions provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) compounds II, compound IV, compound V, compound (c) at least one compound selected from VI, compound VII, compound VIII, compound IX, and compound X, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and (d) at least one compound selected from PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801, and (d) at least one pharmaceutically acceptable carrier.

[0267] In some embodiments, the pharmaceutical compositions provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof; and (b) WO2019 / 195739, WO2019 / 200246, WO2021 / 030555, WO2021 / 030556, WO2017 / 173274, WO2019 / 010092, WO2019 / 018353, WO2010 / 05347 1, WO2011 / 119984, WO2011 / 133751, WO2011 / 133951, WO2015 / 160787, WO2007 / 056341, WO20 09 / 073757, WO2009 / 076142, WO2018 / 107100, WO2019 / 113476, WO2018 / 064632, WO2019 / 1529 40, WO2016 / 057572, WO2021 / 030554, WO2020 / 206080, WO2016 / 105485, U.S. Patent Application Publication No. 2016-0120841, U.S. Patent Application Publication No. 2017-0101405, WO2017 / 009804, WO2018 / 065921, WO2017 / 062581, Journal of Cystic Fibrosis(2018),17(5),595-606, Pedemonte,N.et al.Sci.Adv.2020,6(8),eaay9669, Phuan,P.-W.et al.Sci.Rep.2019,9(1),17640, Bose,S.et al.J.Cyst.Fibros.2020,19 Suppl 1,S25-S32,Crawford,DKJPharmacol.Exp.Ther.2020,374(2),264-272,Brasell,EJet al.PLoS One 2019,14(12),e0223954, Smith,NJ,Solovay,CF,Pharm.Pat.Anal.2017,6(4),179-188,Kunzelmann,K.et al.,Front.Pharmacol.(c) comprising at least one compound selected from those disclosed in 2019,10,3 or Son, J.-H. et al., Eur. J. of Med. Chem. 2020, 112888, and (c) at least one pharmaceutically acceptable carrier.

[0268] In some embodiments, the pharmaceutical compositions provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, and (b) compound II, compound (c) comprising (c) at least two compounds selected from IV, compound V, compound VI, compound VII, compound VIII, compound IX, compound X, PTI-428, ASP-11, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and (c) at least one pharmaceutically acceptable carrier.

[0269] In some embodiments, the pharmaceutical compositions provided herein include (a) compounds of formula I, formula I', formula I'', formula I''', formula Ia, formula IIa, formula IIa', formula IIb, formula IIc, formula IId, formula IIe, formula IIf, formula IIIa, formula IIIa', formula IIIb, formula IIIc, formula IIId, formula IIIe, and formula IIIf, compounds selected from compounds 1 to 53 and compounds 54 to 77, and pharmaceutically acceptable salts and deuterated derivatives thereof, ( b) Compound II, Compound III, Compound III-d, Compound IV, Compound V, Compound VI, Compound VII, Compound VIII, Compound IX, Compound X, PTI-428, ASP-11, ABBV-2222, ABBV- 2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, FDL-169, ARN5562, ARN21586, ARN22081, ARN22652, AR N23765, ARN23766, PTI-801, FDL-176, PTI-808(dirocaftor), GLPG1837, GLPG2451 / ABBV-2451, QBW251(icenticaft or), GLPG3067 / ABBV-3067(Navocaftor), ABBV-191, ELX-02, MRT5005, Lunar-CF, RCT223, Amiloride, ETD001, CF552, GS-9 (c) comprising at least one compound selected from 411, GS-5737, P-1037 (VX-371), P-1055 (VX-551), AZD5634, SPX-101, Ionis-ENaC-2.5Rx, BI1265162, AZ5634, ARO-ENaC1001, ETD002, and DS-1039, as well as pharmaceutically acceptable salts and deuterated derivatives thereof, and (c) at least one pharmaceutically acceptable carrier.

[0270] Any pharmaceutical composition disclosed herein may include at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0271] The pharmaceutical compositions described herein are useful for the treatment of cystic fibrosis and other CFTR-mediated diseases.

[0272] As described above, the pharmaceutical compositions disclosed herein may optionally further include at least one pharmaceutically acceptable carrier. The at least one pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. When used herein, the at least one pharmaceutically acceptable carrier includes any solvent, diluent, other liquid vehicle, dispersing aid, suspension aid, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier becomes incompatible with the compounds of this disclosure, for example, by producing any undesirable biological effect or otherwise interacting in a detrimental manner with any other component of the pharmaceutical composition, its use is intended to be within the scope of this disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin fat, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxymethylcellulose). Examples of ingredients include, but are not limited to, sodium sodium, ethylcellulose, and cellulose acetate, tragacanth powder, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants.

[0273] Compound 11: Heptane solvate In some embodiments, the present invention provides a solvated crystalline form of compound 11. In some embodiments, the solvated crystalline form is heptane solvate. In some embodiments, the present invention provides compound 11 heptane solvate. Figure 1 provides an X-ray powder diffractogram of compound 11 heptane solvate at room temperature.

[0274] In some embodiments, compound 11heptane solvate is substantially pure. In some embodiments, compound 11heptane solvate is substantially crystalline. In some embodiments, compound 11heptane solvate is characterized by an X-ray powder diffractogram produced by X-ray powder diffraction analysis using an incident beam of Cu Kα radiation. In some embodiments, compound 11heptane solvate has many molecules in its asymmetric units. In some embodiments, compound 11heptane solvate is a physical mixture of crystal lattices. In some embodiments, compound 11heptane solvate has a variable amount of heptane in its crystal lattice. In some embodiments, compound 11heptane solvate has a stoichiometric amount of heptane in its crystal lattice. In some embodiments, compound 11heptane solvate has a non-stoichiometric amount of heptane in its crystal lattice.

[0275] In some embodiments, the compound 11-heptane solvate is characterized by an X-ray powder diffractogram having a signal at 5.8 ± 0.2 degrees 2-theta. In some embodiments, the compound 11-heptane solvate is characterized by an X-ray powder diffractogram having a signal at 10.1 ± 0.2 degrees 2-theta. In some embodiments, the compound 11-heptane solvate is characterized by an X-ray powder diffractogram having a signal at 11.7 ± 0.2 degrees 2-theta. In some embodiments, the compound 11-heptane solvate is characterized by an X-ray powder diffractogram having one, two, or three signals selected from 5.8 ± 0.2 degrees 2-theta, 10.1 ± 0.2 degrees 2-theta, and 11.7 ± 0.2 degrees 2-theta.

[0276] In some embodiments, the compound 11 heptane solvate is characterized by an X-ray powder diffractogram having (a) one, two, or three signals selected from 5.8±0.2° 2-theta, 10.1±0.2° 2-theta, and 11.7±0.2° 2-theta, and (b) one, two, three, or four signals selected from 5.6±0.2° 2-theta, 18.1±0.2° 2-theta, 20.5±0.2° 2-theta, and 20.9±0.2° 2-theta. In some embodiments, the compound 11 heptane solvate is characterized by an X-ray powder diffractogram having signals at 5.6±0.2° 2-theta, 5.8±0.2° 2-theta, 10.1±0.2° 2-theta, 11.7±0.2° 2-theta, 18.1±0.2° 2-theta, 20.5±0.2° 2-theta, and 20.9±0.2° 2-theta.

[0277] In some embodiments, the compound 11-heptane solvate is characterized by an X-ray powder diffractogram substantially similar to that in Figure 1.

[0278] In some embodiments, the compound 11 heptane solvate has a peak at 166.3 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 165.8 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 164.6 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 163.4 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 154.8 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 154.0 ± 0.2 ppm. 13It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 152.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 151.6 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 140.2 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 139.4 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 138.5 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 138.0 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 135.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 134.6 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 131.3 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 130.2 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 129.6 ± 0.2 ppm. 13It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 128.5 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 125.7 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 123.7 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 123.2 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 122.9 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 121.1 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 120.2 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 119.2 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 117.8 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 76.2 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 74.4 ± 0.2 ppm. 13It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 73.7 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 73.3 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11heptane solvate has a peak at 40.0 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 38.6 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 37.6 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11heptane solvate has a peak at 36.9 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 35.7 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 33.6 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 32.5 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 32.0 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 30.4 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 30.1 ± 0.2 ppm.13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 29.5 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 28.8 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 28.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 27.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 25.3 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 23.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 22.7 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 22.0 ± 0.2 ppm. 13 It is characterized by having a 13C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 21.6 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 20.3 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 19.6 ± 0.2 ppm. 13It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 18.3 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 17.6 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 13.8 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 13.1 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at 12.5 ± 0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0279] In some embodiments, the heptane solvate of compound 11 is 166.3±0.2 ppm, 165.8±0.2 ppm, 164.6±0.2 ppm, 163.4±0.2 ppm, 154.8±0.2 ppm, 154.0±0.2 ppm, 152.1±0.2 deg ppm, 151.6±0.2 ppm, 140.2±0.2 ppm, 139.4±0.2 ppm, 138.5±0.2 ppm, 138.0±0.2 ppm, 135.1± 0.2ppm, 134.6±0.2ppm, 131.3±0.2ppm, 130.2±0.2ppm, 129.6±0.2ppm, 128.5±0.2ppm, 125.7±0.2ppm, 123.7±0.2ppm m, 123.2±0.2ppm, 122.9±0.2ppm, 121.1±0.2ppm, 120.2±0.2ppm, 119.2±0.2ppm, 117.8±0.2ppm, 76.2±0.2ppm, 74.4± 0.2ppm, 73.7±0.2ppm, 73.3±0.2ppm, 40.0±0.2ppm, 38.6±0.2ppm, 37.6±0.2ppm, 36.9±0.2ppm, 35.7±0.2ppm, 33.6± 0.2ppm, 32.5±0.2ppm, 32.0±0.2ppm, 30.4±0.2ppm, 30.1±0.2ppm, 29.5±0.2ppm, 28.8±0.2ppm, 28.1±0.2ppm, 27.1±0 It has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more peaks selected from 0.2 ppm, 25.3±0.2 ppm, 23.1±0.2 ppm, 22.7±0.2 ppm, 22.0±0.2 ppm, 21.6±0.2 ppm, 20.3±0.2 ppm, 19.6±0.2 ppm, 18.3±0.2 ppm, 17.6±0.2 ppm, 13.8±0.2 ppm, 13.1±0.2 ppm, and 12.5±0.2 ppm. 13 It is characterized by having a C SSNMR spectrum.

[0280] In some embodiments, the compound 11 heptane solvate is substantially similar to that shown in Figure 3. 13 It is characterized by a C SSNMR spectrum.

[0281] In some embodiments, the compound 11 heptane solvate has a peak at -63.5 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -63.8 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -65.1 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -65.8 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -66.3 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -67.0 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -74.0 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -74.9 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has a peak at -76.6 ± 0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0282] In some embodiments, the compound 11 heptane solvate has one, two, or three peaks selected from -65.1±0.2 ppm, -67.0±0.2 ppm, and -76.6±0.2 ppm. 19The compound is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has one, two, three, four, or five peaks selected from -63.5±0.2 ppm, -65.1±0.2 ppm, -67.0±0.2 ppm, -74.9±0.2 ppm, and -76.6±0.2 ppm. 19 The compound is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has 1, 2, 3, 4, 5 or more peaks selected from -63.5±0.2 ppm, -63.8±0.2 ppm, -65.1±0.2 ppm, -65.8±0.2 ppm, -66.3±0.2 ppm, -67.0±0.2 ppm, -74.0±0.2 ppm, -74.9±0.2 ppm, and -76.6±0.2 ppm. 19 The compound 11-heptane solvate is characterized by having an F SSNMR spectrum. In some embodiments, the compound 11-heptane solvate has 1, 2, 3, 4, 5 or more peaks selected from -63.5±0.2 ppm, -63.8±0.2 ppm, -65.1±0.2 ppm, -65.8±0.2 ppm, -66.3±0.2 ppm, -67.0±0.2 ppm, -74.0±0.2 ppm, -74.9±0.2 ppm, -76.6±0.2 ppm, and -77.6±0.2 ppm. 19 It is characterized by having an F SSNMR spectrum.

[0283] In some embodiments, the compound 11 heptane solvate is substantially similar to that shown in Figure 4. 19 It is characterized by an F SSNMR spectrum.

[0284] Another aspect of the present invention provides a process for preparing a solvated crystalline solid form of compound 11, comprising dissolving compound 11 in one or more solvents to form a mixture, and crystallizing the compound from the mixture. In some embodiments, the one or more solvents include heptane. In some embodiments, the one or more solvents include heptane and dichloromethane.

[0285] Another aspect of the present invention provides a method for preparing compound 11 heptane solvate. In some embodiments, the method for preparing compound 11 heptane solvate comprises (i) dissolving compound 11 in heptane and dichloromethane to form a mixture, (ii) concentrating the mixture, (iii) collecting a solid from the mixture, and (iv) drying the collected solid. In some embodiments, (ii) optionally includes swirling the mixture at room temperature. In some embodiments, (iii) optionally includes rinsing the recovered solid with cold heptane. In some embodiments, the method for preparing compound 11 heptane solvate comprises dissolving compound 11 in heptane and dichloromethane, concentrating under rotational evaporation, swirling at room temperature, filtering the solid, washing the solid with cold heptane, and drying under vacuum to obtain compound 11 heptane solvate.

[0286] Non-exclusive exemplary embodiments 1. A compound selected from the compounds of formula I, [ka] During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these can independently be hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), C3-C8 cycloalkyl, C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atomY These two cases combine to form a ring selected from C3-C8 cycloalkyl and 3-6 membered heterocyclyl, or one exists on one atom and the other on an adjacent atom R Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2)2, -CN, phenyl, benzyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, where ring C is C6-C 10 Selected from aryls and 5-10 membered heteroaryls, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, 7, and 8. Compounds in which m is selected from 0, 1, 2, and 3, as well as their deuterated derivatives and pharmaceutically acceptable salts. 2.X is selected from -O-, -S-, -SO-, and -SO2-, Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these is independently hydrogen, C1-C6 alkyl (optionally substituted with 1 to 6 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, and 7. Compounds in which m is selected from 0, 1, 2, and 3, as well as their deuterated derivatives and pharmaceutically acceptable salts. 3. A compound, deuterated derivative, or pharmaceutically acceptable salt according to Embodiment 1 or 2, wherein X is -O-. 4. Each Y is independent, -C(R Y )2-, -CO-, and [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 3. 5.R Y Each of these is independently substituted with hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 4. 6.R Y Each of them operates independently, hydrogen, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 5. 7. Q is independent of each other, ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups.10 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from aryl compounds according to any one of Embodiments 1 to 6. 8. Q is independent of each other, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 7. 9. C6-C in which ring B is optionally substituted with 1 to 3 groups independently selected from the halogen. 10 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from aryl compounds according to any one of Embodiments 1 to 8. 10. Ring B is, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of Embodiments 1 to 9. 11.-(Y) n -but, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 10, which is a group selected from the above. 12. Y is -C(R Y A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 11, wherein the compound is 2-. 13.R 1 Each of them operates independently, -CF3 and -N(R 2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 12, selected from 2. 14.R 2 Each of these is independently selected from hydrogen and C1-C6 alkyl, and comprises a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 13. 15.R 2A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 14, wherein each of the atoms is hydrogen. 16.Z [ka] The compound, deuterated derivative, or pharmaceutically acceptable salt described in any one of Embodiments 1 to 15. 17.R Z1 However, the compounds, deuterated derivatives, or pharmaceutically acceptable salts described in any one of Embodiments 1 to 16 are selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens). 18.R Z1 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 17, wherein is -CF3. 19.R Z2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 18, wherein is hydroxyl. 20.n is a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 19, selected from 4, 5, and 6. 21. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 20, wherein n is 6. 22.m is a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 21, selected from 1 and 2. 23. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 1 to 22, wherein m is 2. 24. A compound selected from the compounds of formula Ia, [ka] During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NR Y1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these can be independently a halogen, a C1-C6 alkyl (which can be optionally substituted with 1 to 6 groups independently of the halogen), or an OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2 )2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these independently consists of hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1-6 groups independently selected from halogens or 1-3 hydroxyls), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. Compounds in which n is selected from 4, 5, 6, and 7, as well as their deuterated derivatives and pharmaceutically acceptable salts. 25. The compound, deuterated derivative, or pharmaceutically acceptable salt described in Embodiment 24, wherein X is -O-. 26. Each Y is independent, -C(R Y )2-, -CO-, and [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in Embodiment 24 or 25. 27.R Y Each of these is independently substituted with hydrogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and -OR Y1 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of embodiments 24 to 26. 28.R Y Each of them operates independently, hydrogen, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of embodiments 24 to 27. 29. Q is independent of each other, ■C3-C8 cycloalkyl, ■C6-C alkyl groups are optionally substituted with 1 to 3 groups independently selected from halogens and C1-C6 alkyl groups. 10 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from aryl compounds according to any one of embodiments 24 to 28. 30.Q each operates independently, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of embodiments 24 to 29. 31. C6-C in which ring B is optionally substituted with 1 to 3 groups independently selected from the halogen. 10 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from aryl compounds according to any one of embodiments 24 to 30. 32. Ring B is, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt selected from any one of embodiments 24 to 31. 33.-(Y) n -but, [ka] A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 32, which is a group selected from the above. 34.Y is -C(R Y A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 33, wherein the compound is 2-. 35.R 1 Each of them operates independently, -CF3 and -N(R 2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 34, selected from 2. 36.R 2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24 to 35, wherein each is independently selected from hydrogen and C1-C6 alkyl. 37.R 2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 36, wherein each of the atoms is hydrogen. 38.Z [ka] The compound, deuterated derivative, or pharmaceutically acceptable salt described in any one of embodiments 24 to 37. 39.R Z1 However, the compounds, deuterated derivatives, or pharmaceutically acceptable salts described in any one of Embodiments 24 to 38 are selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens). 40.R Z1 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 39, wherein is -CF3. 41.R Z2 A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24 to 40, wherein is hydroxyl. 42.n is a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of embodiments 24 to 41, selected from 4, 5, and 6. 43. A compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of Embodiments 24 to 42, wherein n is 6. 44. A compound selected from the compounds of formula IIa, formula IIb, and formula IIc, [ka] During the ceremony, X is selected from -O-, -S-, -SO-, and -SO2-. Y is independent of each other, -C(R Y )2-, -O-, -CO-, and [ka] Selected from, R Y Each of these independently consists of hydrogen, halogen, C1-C6 alkyl (optionally substituted with 1-3 groups independently selected from hydroxyl and Q), and C6-C 10 Aryl, 5-10 member heteroaryl, -OR Y1 , -CO2R Y1 , -COR Y1 , -CON(R Y1 )2, and -NRY1 - Selected from or R on the same atom Y These two cases come together, C 3- R forms a ring selected from C8 cycloalkyl and 3- to 6-membered heterocyclines, or one of them is located on one atom and the other is located on an adjacent atom. Y These two cases combine to form a π bond, R Y1 Each of these is independently selected from hydrogen and C1-C6 alkyl, or R bonded to the same nitrogen. Y1 These two cases combine to form a 3-6 member heterocycline. Ring B is ■C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens, C1-C6 alkyls, and C1-C6 alkoxys), ■C3-C8 cycloalkyl, ■ 5-10 member heteroaryls, and ■Selected from 3-6 membered heterocyclines (which are arbitrarily substituted with 1-3 groups independently selected from C1-C6 alkyl groups), Each Q is independent, ■C1-C6 alkyl, 〇Halogen, Oxo, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from halogens and -OCF3), and 〇C3-C8 cycloalkyl, ■C3-C8 cycloalkyl, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens, -NH2, and -NHCOMe), 〇C1-C6 alkoxy, 〇C6-C 10 Aryl (optionally substituted with 1 to 3 groups independently selected from C1-C6 alkyl groups), and 〇C3-C8 cycloalkyl, ■C6-C 10 It is Ariel, 〇Halogen, 〇CN, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), ○C1-C6 alkoxy, ■Halogen, ■C1-C6 alkoxy groups, which are optionally substituted with 1 to 4 groups independently selected from C3-C8 cycloalkyl groups (optionally substituted with CF3). ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 groups independently selected from halogens, CF3, OCF3, and C1-C6 alkyl groups), and 〇C6-C 10 C6-C is optionally substituted with 1 to 3 groups independently selected from the aryl group. 10 Ariel, ■A 5-10 member heteroaryl, 〇Halogen, ○ C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), ○C3-C8 cycloalkyl (optionally substituted with 1 to 3 CF3 groups), and ○ 5-10 member heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 member heterocyclils. ■3-10 member heterocyclines, ○C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from oxo and C3-C8 cycloalkyl groups), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R 1 Each of these operates independently: halogen, -CF3, -OR 2 , -N(R 2 )2, -CO2R 2 ,-CO-N(R 2)2, -CN, phenyl, benzyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, 5-6 member heteroaryl, 3-6 member heterocyclyl, -SO2R 2 , -SR 2 -SOR 2 , -PO(OR 2 )2, and -PO(R 2 ) Selected from 2, R 2 Each of these independently consists of hydrogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from the halogen), and C6-C 10 Selected from aryl groups (optionally substituted with C1-C6 alkoxy groups, which are optionally substituted with 1 to 6 groups independently selected from halogens), Z [ka] Selected from, R Z1 However, selected from hydrogen, -CN, C1-C6 alkyl (optionally substituted with 1 to 3 groups independently selected from halogen or hydroxyl), 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered aryl, and 5-6 membered heteroaryl, R Z2 However, it is selected from hydrogen, halogen, and hydroxyl, or R Z1 and R Z2 Together, they form a group selected from oxo and =N-OH, R Z3 Each of these independently comprises hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, and C6-C 10 Selected from the aryl, or R Z3 These two cases combine to form a 3-6 member heterocycline. Compounds in which m is selected from 0, 1, 2, and 3, as well as their deuterated derivatives and pharmaceutically acceptable salts. 45.m is a compound, deuterated derivative, or pharmaceutically acceptable salt of Embodiment 44, selected from 1 and 2. The compound, deuterated derivative, or pharmaceutically acceptable salt according to embodiment 44 or 45, wherein m is 2. 47. A compound selected from the compounds of formula IId, formula IIe, and formula IIf,

Chemical formula

Chemical formula

Chemical formula

[0287] General experimental procedure Abbreviation ACN: Acetonitrile Acetic acid (TOH) BCl3: Boron trichloride Boc anhydrous ((Boc)2O): ditert-butyl dicarbonate CDCl3:Chloroform-d CDI: 1,1'-Carbonyldiimidazole CD3OD: Methyl-d3 alcohol-d CH2Cl2: Dichloromethane CH3CN: Acetonitrile CO2: Carbon dioxide Cs2CO3: Cesium Carbonate CuBr2: Copper(II) bromide CuI: Copper(I) iodide DCE: 1,2-Dichloroethane DCM: Dichloromethane DDQ:2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DI: Deionization DIAD: Diisopropyl azodicarboxylate DIEA:DIPEA; N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 EA: Ethyl acetate ELSD: Evaporative Light Scattering Detector Et2O: Diethyl ether æ:ethyl acetate EtOH: Ethanol ESI-MS: Electrospray Ionization Mass Spectrometry First-generation Grubbs catalyst: Dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II) Second-generation Grubbs catalyst: [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxyphenyl)methylene]ruthenium H2: Hydrogen HATU:N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide HCl: Hydrochloric acid HFIP: Hexafluoroisopropanol Second-generation Hoveyda-Grubbs catalyst: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II) HPLC: High-Performance Liquid Chromatography IPA: Isopropanol IPAC: Isopropyl acetate iPrOH: Isopropanol KHSO4: Potassium sulfite LC: Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry LDA: Lithium diisopropylamide LiOH: Lithium hydroxide MeCN: Acetonitrile MeTHF or 2-MeTHF:2-methyltetrahydrofuran MeOH: methanol MTBE: Methyl tert-butyl ether MgSO 4: Magnesium sulfate n-BuLi:n-butyllithium NaBH 4: Sodium borohydride NaHCO3: Sodium Bicarbonate NaHMDS: Sodium bis(trimethylsilyl)amide NaOH: Sodium hydroxide Na2S2O 3: Sodium thiosulfate Na2SO4: Sodium sulfate NBS: N-bromosuccinimide NMP:N-methyl-2-pyrrolidone NMR: nuclear magnetic resonance Pd / C: Palladium Carbon Pd(OAc)2: Palladium(II) acetate rt: room temperature SFC: Supercritical Fluid Chromatography Silica Cat Pd: Palladium Silica SilicaMetS: Silica-supported metal scavenger SiO2: Silica gel T3P: 1-Propanephosphonic Acid Anhydride TBAI: Tetrabutylammonium iodide TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran UPLC: Ultra-high-performance liquid chromatography Xanthophos:4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos Pd G3: (2-Dicyclohexylphosphino-2',4',6'-Triisopropyl-1,1'-Biphenyl)[2-(2'-Amino-1,1'-Biphenyl)]Palladium(II) Methanesulfonate Zhan catalyst-1B: Dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)

[0288] General method Unless otherwise specified, reagents and starting materials were obtained from commercial sources and used without purification.

[0289] Proton and carbon NMR spectra were obtained at 400 MHz and 100 MHz, respectively. 1 H resonance frequency and 13 The spectra were acquired using either a Bruker Biospin DRX 400MHz FTNMR spectrometer or a 300MHz NMR spectrometer operating at the ¹¹¹ C resonance frequency. One-dimensional proton and carbon spectra were acquired using a broadband observation (BBFO) probe with a 20Hz sample rotation and digital resolutions of 0.1834Hz / Pt and 0.9083Hz / Pt, respectively. All proton and carbon spectra were acquired under temperature control at 30°C using standard, previously published pulse sequences and customary processing parameters.

[0290] NMR (one-dimensional and two-dimensional) spectra were also recorded using a Bruker AVNE 400MHz spectrometer, equipped with a 5mm multinuclear Iprobe and operating at 400MHz and 100MHz, respectively.

[0291] The NMR spectrum was obtained using a pulse angle of 45 degrees, a spectral width of 4800 Hz, and 28860 acquisition points. 1 For H, recordings were also made using a 300 MHz Varian Mercury NMR instrument. The FID was zero-packed up to 32k points, and a 0.3 Hz linewidth expansion was applied before the Fourier transform. 19 The F NMR spectrum was recorded at 282 MHz using a pulse angle of 30 degrees, a spectral width of 100 kHz, and 59,202 acquisition points. The FID was zero-packed to 64 k points, and a linewidth expansion of 0.5 Hz was applied before the Fourier transform.

[0292] The NMR spectrum was obtained using a pulse angle of 30 degrees, a spectral width of 8000 Hz, and an acquisition point of 128 k. 1 For H, recordings were also made using a 400 MHz Bruker Avance III HD NMR instrument. The FID was zero-packed up to 256 k points, and a 0.3 Hz linewidth expansion was applied before the Fourier transform. 19 The F NMR spectrum was recorded at 377 MHz using a pulse angle of 30 degrees, a spectral width of 89286 Hz, and acquisition points at 128 k. The FID was zero-packed up to 256 k points, and a linewidth expansion of 0.3 Hz was applied before the Fourier transform.

[0293] NMR spectra were also recorded using a Bruker AC 250MHz instrument equipped with a 5mm QNP(H1 / C13 / F19 / P31) probe (Type: 250-SB, s#23055 / 0020) or a Varian 500MHz instrument equipped with a 5mm ID PFG 50-202 / 500MHz probe (Model / Part Number 99337300).

[0294] Unless otherwise specified in the following examples, the final purity of the compounds was measured using Waters' Acquity UPLC BEH C18 The purity was determined by reversed-phase ULC using a column (50 × 2.1 mm, particle size 1.7 μm) (product number: 186002350) and a double gradient run of 1%-99% mobile phase B over 3.0 minutes. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = CH3CN (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60°C. Final purity was calculated by averaging the area under the curve (AUC) of two UV traces (220 nm, 254 nm). Low-resolution mass spectra were obtained using a single quadrupole mass spectrometer with an electrospray ionization (ESI) source capable of achieving a mass accuracy of 0.1 Da and a minimum resolution of 1000 (no resolution units) across the detection range [M+1]. + It was reported as a species.

[0295] Solid-state NMR (SSNMR) spectra were recorded using a Bruker-Biospin 400 MHz wide-bore spectrometer equipped with a Bruker-Biospin 4 mm HFX probe. The sample was packed into a 4 mm ZrO2 rotor and spun under magnetic angular spinning (MAS) conditions, including a spin velocity typically set to 12.5 kHz. The proton relaxation time was... 13 To set the probe recycle delay for a C-cross polarization (CP) MAS experiment, 1 The fluorine relaxation time was measured using the H MAS T1 saturation recovery relaxation experiment. 19 To set the probe recycling delay for the F MAS experiment, 19 Measurements were performed using the F MAS T1 saturation recovery relaxation experiment. The CP contact time for the carbon CPMAS experiment was set to 2 milliseconds. A CP proton pulse with a linear ramp (50%~100%) was used. The carbon Hartmann-Hahn agreement was optimized with an external reference sample (glycine). Both carbon and fluorine spectra were recorded by proton decoupling using a TPPM15 decoupling array with an electric field strength of approximately 100 kHz. General synthesis scheme

[0296] Another aspect of this disclosure provides compounds of formulas I, I', I'', I''', Ia, IIa, IIa', IIb, IIc, IId, IIe, IIf, IIIa, IIIa', IIIb, IIIc, IIId, IIIe, and IIIf, compounds 1-53, compounds 54-77, and pharmaceutically acceptable salts of any of these compounds, deuterated derivatives of any of the foregoing, and methods for producing intermediates for producing any of the foregoing. In some embodiments of the following schemes and examples, the nitrogen atom and the oxygen atom may each optionally have one or more protecting groups selected from the range of protecting groups disclosed herein, in addition to or instead of the specified variable substituents. In some embodiments of the following schemes and examples, each compound may be replaced by a deuterated derivative.

[0297] Scheme 1 [ka] Scheme 1 refers to a process for preparing intermediate compounds of formula S1-7 from compounds of formula S1-1. Alk is selected from C1-C6 linear or branched alkyl groups. 1 The halogens are selected from Cl, I, or Br. Y and R Y This is defined in equation I above.

[0298] The compound of formula S1-1 can be reacted with the compound of formula S1-2 to form the compound of formula S1-3 using any conditions suitable for Grignard addition. For example, the Grignard addition of the compound of formula S1-1 with the compound of formula S1-2 can be carried out in Et2O at -78°C, and then an aqueous solution of 1N HCl can be added to obtain the compound of formula S1-3. The conversion from the compound of formula S1-3 to the compound of formula S1-4 can be achieved by any suitable benzylation procedure. The conversion from the ester of formula S1-4 to the carboxylic acid of formula S1-5 can be achieved by any suitable hydrolysis conditions. For example, the conversion from the carboxylic acid of formula S1-5 to the compound of formula S1-6 can be achieved by reacting the compound of formula S1-5 with HATU and Et3N in DMF, and then adding tert-butyl N-aminocarbamate. The carbamate of formula S1-6 can be converted to the hydrazide of formula S1-7 using any suitable hydrolysis conditions. For example, the compound of formula S1-7 can be obtained by reacting the compound of formula S1-6 with HCl in CH2Cl2 at ambient temperature.

[0299] Scheme 2 [ka] Scheme 2 refers to the process for preparing the intermediate compound of formula S2-3 from the compound of formula S2-1. A1 is -X-(Y) 2-4 -C(R Y )=C(R Y ) Selected from 2, -OH, -OPG (wherein PG is a preferred protecting group), and halogens. 1 , m, X, Y, and R Y This is defined in equation I above.

[0300] The compound of formula S2-2 can be obtained from the compounds of formula S2-1 and S1-7 using any conditions suitable for the formation of an amide bond. For example, the compound of formula S2-1 can be reacted with CDI in acetonitrile and DMF, and then the compound of formula S1-7 can be added to obtain the compound of formula S2-2. The compound of formula S2-2 can be converted to the compound of formula S2-3 using any conditions suitable for oxadiazole formation. For example, the compound of formula S2-2 can be reacted with DIPEA in acetonitrile, and then p-toluenesulfonyl chloride can be added to obtain the compound of formula S2-3.

[0301] Scheme 3 [ka] Scheme 3 refers to a process for preparing the compound of formula S3-8 from the compound of formula S3-1. Alk is selected from C1-C6 linear or branched alkyl groups. LG is selected from halogens and oxygen-based leaving groups such as OTf. 1 , m, Y, and R Y This is defined in equation I above.

[0302] Compound S3-3 can be obtained by reacting the compound of formula S3-1 with the compound of formula S3-2 under any suitable aromatic substitution conditions. For example, compound S3-2 can be reacted with sodium hydride in DMF, and then compound S3-1 can be added to obtain compound S3-3. The conversion from the ester of formula S3-3 to the carboxylic acid of formula S3-4 can be achieved under any suitable hydrolysis conditions. Compound S3-5 can be prepared from the compounds of formula S3-4 and S1-7 using any suitable amide bond formation conditions. Compound S3-5 can be converted to compound S3-6 using any suitable conditions for oxadiazole formation. For example, compound S3-5 can be reacted with methoxycarbonyl-(triethylammonio)sulfonyl azanide in THF to obtain oxadiazole S3-6. Macrocyclization of compound S3-6 can be achieved under any suitable ring closure metathesis conditions. For example, the compound of formula S3-6 is reacted in DCE in the presence of [1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichloro-[(2-isopropoxy-5-nitrophenyl)methylene]ruthenium to obtain the E / Z isomer ( [ka] The macrocyclic compounds of formula S3-7 can be obtained as a mixture of (as indicated by the bonding) components. The conversion from the unsaturated compounds of formula S3-7 to the macrocyclic compounds of formula S3-8 can be achieved using any procedure suitable for olefin reduction and benzyl deprotection.

[0303] Scheme 4 [ka] Scheme 4 refers to a process for preparing the compound of formula S4-4 from the compound of formula S4-1. LG is selected from oxygen-based leaving groups such as halogens, hydroxyls, and OTf. 1 , m, Y, and R Y This is defined in equation I above.

[0304] The compound of formula S4-1 can be reacted with the compound of formula S3-2 by any suitable aromatic substitution conditions or Mitsunobu reaction to obtain the compound of formula S4-2. For example, the compound of formula S4-1 can be reacted with the alcohol of formula S3-2, cesium carbonate, and copper iodide in DMSO. Macrocyclization of the compound of formula S4-2 can be achieved by any suitable ring closure metathesis conditions. For example, the compound of formula S4-2 can be reacted in DCE in the presence of a second-generation Grubbs catalyst to obtain the E / Z isomer ( [ka] The macrocyclic compound of formula S4-3 can be obtained as a mixture of (as indicated by the bond). The conversion from the unsaturated compound of formula S4-3 to the macrocyclic compound of formula S4-4 can be achieved using any procedure suitable for olefin reduction and benzyl deprotection.

[0305] Scheme 5 [ka] Scheme 5 refers to the process for preparing the compounds of formula S5-3, S5-6, and S5-7 from the compound of formula S5-1. 1 m and Y are as defined in equation I above.

[0306] The conversion of the compound of formula S5-1 to the deuterated compound of formula S5-2 can be achieved by any suitable catalytic deuterating conditions. For example, the compound of formula S5-1 can be reacted with 10% palladium carbon in CD3OD under a deuterium gas atmosphere to obtain the compound of formula S5-2. The conversion of the benzyl-protected compound of formula S5-2 to the free alcohol of formula S5-3 can be achieved by any suitable deprotection conditions.

[0307] The conversion of the unsaturated compound of formula S5-1 to the alcohol of formula S5-4 can be achieved by any suitable hydrogenation / oxidation conditions. For example, the compound of formula S5-1 can be reacted with a boranedimethyl sulfide complex in THF, then quenched with an aqueous NaOH solution, and hydrogen peroxide can be added to obtain the alcohol of formula S5-4 as a mixture of positional isomers. The compound of formula S5-4 can be debenzylated using any suitable benzyl deprotection conditions to obtain the compound of formula S5-5. The conversion of the compound of formula S5-5 to the compound of formula S5-7 can be achieved by any suitable oxidation conditions. For example, the compound of formula S5-5 can be reacted with NaHCO3 and Dess-Martin periodinane in CH2Cl2 to obtain the compound of formula S5-7.

[0308] Alternatively, the conversion from the compound of formula S5-4 to the compound of formula S5-6 can be achieved by any suitable oxidation conditions. For example, the compound of formula S5-4 can be reacted with dess-martinperiodinane in CH2Cl2 to obtain the compound of formula S5-6. The compound of formula S5-6 can be debenzylated using any suitable benzyl deprotection conditions to obtain the compound of formula S5-7.

[0309] Scheme 6 [ka] Scheme 6 refers to a process for preparing the compound of formula S6-5 from the compound of formula S6-1. LG is selected from halogens and oxygen-based leaving groups such as OTf. 1 , m, Y, and R Y This is defined in equation I above.

[0310] The conversion of compounds of formula S6-1 and S6-2 to the compound of formula S6-3 can be achieved by any suitable aromatic substitution conditions. For example, the compound of formula S6-1 can be reacted with the compound of formula S6-2 and DMSO. Macrocyclization of the compound of formula S6-3 can be achieved by any suitable ring closure metathesis conditions. For example, the compound of formula S6-3 can be reacted in DCE in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium and tricyclohexylphosphan to obtain the E / Z isomer ( [ka] The macrocyclic compound of formula S6-4 can be obtained as a mixture of (as indicated by the bond). The conversion from the unsaturated compound of formula S6-4 to the macrocyclic compound of formula S6-5 can be achieved using any procedure suitable for olefin reduction and benzyl deprotection.

[0311] Scheme 7 [ka] Scheme 7 refers to the process for preparing the compound of formula S7-6 from the compound of formula S7-1. 1 , m, Y, and R Y This is defined in formula I above. LG is selected from halogens and oxygen-based leaving groups such as OTf.

[0312] The compound of formula S7-1 can be reacted with the compound of formula S7-2 by any suitable lithiation procedure to form the compound of formula S7-3. For example, the reaction of the compound of formula S7-1 and the compound of formula S7-2 can be carried out in n-BuLi and ether at -78°C to form the compound of formula S7-3. The conversion from the compound of formula S7-3 to the compound of formula S7-4 can be achieved by any suitable ring closure metathesis procedure. For example, the ring closure metathesis reaction of the compound of formula S7-3 can be achieved in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium in DCE and tricyclohexylphosphine to form the E / Z isomer ( [ka] The compound of formula S7-4 can be obtained as a mixture of (indicated by the bond). The conversion from the compound of formula S7-4 to the compound of formula S7-5 can be achieved by any procedure suitable for olefin reduction and benzyl deprotection. The conversion from the compound of formula S7-5 to the compound of formula S7-6 can be achieved by any procedure suitable for oxidation from thioether to sulfoxide.

[0313] Scheme 8 [ka] Scheme 8 refers to a process for preparing the compound of formula S8-8 from the compound of formula S8-1. Alk is selected from C1-C6 linear or branched alkyl groups. LG is selected from oxygen-based leaving groups such as OTf and halogens such as Cl, I, and Br. 1 , m, Y, R Y Ring B is defined in equation I above.

[0314] Using any conditions suitable for the synthesis of aryl ethers from alcohols and aryl halides, the compound of formula S8-1 can be reacted with the compound of formula S8-2 to obtain the compound of formula S8-3. Using any conditions suitable for the condensation of hydrazides with carboxylic acids, the compound of formula S8-3 can be reacted with the compound of formula S8-4 to form the compound of formula S8-5. Using any conditions suitable for the formation of oxadiazoles from hydrazides, the compound of formula S8-5 can be converted to the compound of formula S8-6. The conversion from the compound of formula S8-6 to the compound of formula S8-7 can be achieved by any suitable ring closure metathesis procedure. For example, the ring closure metathesis reaction of the compound of formula S8-6 can be achieved in the presence of benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium in DCE and tricyclohexylphosphine to obtain the E / Z isomer ( [ka] The compound of formula S8-7 can be obtained as a mixture of (indicated by the bond). The conversion from the compound of formula S8-7 to the compound of formula S8-8 can be achieved by any procedure suitable for olefin reduction and benzyl deprotection.

[0315] Scheme 9 [ka] Scheme 9 refers to a process for preparing compounds of formula S9-6 and S9-7 from the compound of formula S9-1. 1 , m, Y, R Y , and ring B are as defined in formula I above. LG is selected from oxygen-based leaving groups such as OTf and halogens such as Cl, I, and Br. x This is selected from halogens such as Cl, I, or Br.

[0316] The compound of formula S9-1 can be reacted with the compound of formula S9-2 to obtain the compound of formula S9-3 using any conditions suitable for the synthesis of aryl ethers from alcohols and aryl halides. The conversion of the compound of formula S9-3 to the compound of formula S9-4 and / or the compound of formula S9-5 can be achieved by any suitable cross-coupling procedure. For example, the macrocyclization reaction of the compound of formula S9-3 can be achieved in the presence of palladium(II) acetate, tris-o-tolylphosphan, and triethylamine in acetonitrile to obtain the compound of formula S9-4 and / or the compound of formula S9-5. The conversion of the compound of formula S9-4 to the compound of formula S9-6 and the conversion of the compound of formula S9-5 to the compound of formula S9-7 can be achieved by any procedure suitable for olefin reduction and benzyl deprotection.

[0317] Scheme 10 [ka] Scheme 10 refers to a process for preparing the compound of formula S10-6 from the compound of formula S10-1. 1 , m, Y, R Y , and ring B are defined in formula I above. L x This is selected from halogens such as Cl, I, or Br.

[0318] The compound of formula S10-1 can be reacted with the compound of formula S10-2 to form the compound of formula S10-3 using any suitable oxadiazole formation procedure. For example, the compound of formula S10-1 can be reacted with the compound of formula S10-2 and (isocyanoimino)triphenylphosphoran to obtain the compound of formula S10-3. The conversion from the compound of formula S10-3 to the compound of formula S10-4 can be achieved by any suitable cross-coupling procedure. For example, the macrocyclization reaction of the compound of formula S10-3 can be achieved in the presence of palladium(II) acetate, tris-o-tolylphosphan, and triethylamine in acetonitrile to obtain the E / Z isomer ( [ka] The compound of formula S10-4 can be obtained as a mixture of (indicated by the bond). The conversion from the compound of formula S10-4 to the compound of formula S10-5 can be achieved by any procedure suitable for olefin reduction.

[0319] Synthesis procedure for common intermediates Preparation of intermediate 1:6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] Step 1: 1-Oxide-5-(trifluoromethyl)pyridine-1-ium-2-carboxylate methyl [ka] Urea hydrogen peroxide (62.7 g, 646.53 mmol) was added in small amounts at 0°C to a stirred solution of methyl 5-(trifluoromethyl)pyridine-2-carboxylate (40 g, 191.09 mmol) in 1,2-dichloroethane (300 mL). Then, trifluoroacetic anhydride (107.70 g, 72 mL, 507.65 mmol) was added over 30 minutes at -10°C using a cooling bath (CO2 / acetone bath). The reaction mixture was then stirred at 0°C for another 30 minutes, and then stirred at ambient temperature for 1 hour. The reaction mixture was then poured into cooled ice water (600 mL). The mixture was diluted with dichloromethane (300 mL), and the layers were separated. The aqueous phase was extracted with dichloromethane (2 × 200 mL). The combined organic phases were washed with water (2 × 300 mL) and brine (1 × 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain methyl 1-oxide-5-(trifluoromethyl)pyridine-1-ium-2-carboxylate (47.6 g, 90%) as a pale yellow solid. 1 H NMR (300MHz, DMSO-d6) δ 8.89 (s, 1H), 8.02-7.90 (m, 1H), 7.86-7.72 (m, 1H), 3.89 (s, 3H) ppm. 19F NMR(282MHz,DMSO-d6)δ-62.00(s,3F)ppm. ESI-MS m / z calculated value 221.02998, measured value 222.1(M+1) + ;Retention time: 1.24 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0320] Step 2: 6-Hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] Trifluoroacetic anhydride (291.62 g, 193 mL, 1.3885 mol) was added dropwise at 0°C to a mixture of methyl 1-oxide-5-(trifluoromethyl)pyridine-1-ium-2-carboxylate (51.058 g, 230.66 mmol) in DMF (305 mL). The mixture was then stirred overnight at room temperature. The mixture was concentrated under reduced pressure to remove excess trifluoroacetic acid. The remaining DMF solution was added dropwise to 1000 mL of stirred water cooled to 0°C. The precipitated solid was collected by filtration and then washed with water (300 mL). The solid was dried under high vacuum to obtain methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (45.24 g, 86%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 7.90(d,J=7.2Hz,1H),7.03(d,J=7.2Hz,1H),4.02(s,3H)ppm. 19 F NMR(282MHz,DMSO-d6)δ-66.39(s,3F)ppm. ESI-MS m / z calculated value 221.03, measured value 222.1(M+1) + ;Retention time: 1.43 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0321] Step 3: 6-Hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] To a 200 mL 18.4 M 3.6800 mol ice-cold sulfuric acid solution of methyl 6-hydroxy-5-(trifluoromethyl)pyridine-2-carboxylate (33.04 g, 149.41 mmol), nitric acid (13 mL 15.8 M, 205.40 mmol) was added dropwise. After 5 minutes, the ice bath was removed, and the reaction mixture was stirred overnight at 38°C. When the reaction was not complete, 3 mL 15.8 M 47.400 mmol of nitric acid was added dropwise at room temperature, and the reaction mixture was heated at 38°C for 4.5 hours. The reaction mixture was slowly poured into 900 mL of ice-cold water, and the mixture was cooled at 0°C for 15 minutes. The resulting solid was then isolated by filtration and washed with water (600 mL). The solid was dried overnight under high vacuum to obtain methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (39.49 g, 99%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.54 (s, 1H), 3.95 (s, 3H) ppm. 19 F NMR(282MHz,DMSO-d6)δ-64.56(s,3F)ppm. ESI-MS m / z calculated value 266.0151, measured value 267.1(M+1) + ;Retention time: 1.64 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0322] Step 4: 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate methyl carboxylate [ka] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (10 g, 37.575 mmol) and phenyl dichlorophosphate (48.008 g, 34 mL, 227.55 mmol) was heated at 170°C for 90 minutes. After cooling to room temperature, the mixture was diluted with ethyl acetate (400 mL) and washed with brine (2 × 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (0%-15% ethyl acetate / heptane) yielded methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (5.45 g, 50%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ 8.75(s,1H),4.07(s,3H)ppm. 19 F NMR (282 MHz, CDCl3) δ -64.12 (s, 3F) ppm. ESI-MS m / z calculated value 283.9812, measured value 285.0 (M+1). + ;Holding time: 1.95 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0323] Preparation of intermediate 2:6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] Step 1: 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] A mixture of methyl 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (32 g, 120.24 mmol) in THF (180 mL) and water (180 mL) was treated with lithium hydroxide monohydrate (15.14 g, 360.79 mmol) and stirred overnight at 27 °C. The crude reaction mixture was cooled to room temperature, the pH was adjusted to 2 with 0.5 M aqueous hydrochloric acid (380 mL), and then transferred to a 1 L separatory funnel containing 2-methyl THF for extraction. The layers were separated, and the organic layer was washed with water (150 mL) and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6-hydroxy-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (29.61 g, 96%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.45(s,1H)ppm. 19 F NMR(282MHz,DMSO-d6)δ-64.53(s,3F)ppm. ESI-MS m / z calculated value 251.9994, measured value 253.0(M+1) + ;Retention time: 0.79 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0324] Preparation of intermediate 3:6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] Step 1: 6-Chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] To a solution of methyl 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylate (1.14 g, 4.006 mmol) in THF (48.51 mL) and water (24.26 mL), lithium hydroxide monohydrate (201.7 mg, 4.807 mmol) was added at 0°C. The reaction mixture was heated to room temperature and then stirred for 2 hours. 1N HCl was added to acidify the solution to a pH of approximately 2-3, and then extracted with ethyl acetate. The organic phase was washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to obtain a clear syrup of 6-chloro-3-nitro-5-(trifluoromethyl)pyridine-2-carboxylic acid (1.05 g, 97%). ESI-MS m / z calculated value: 269.9655, measured value: 271.0 (M+1) + Holding time: 0.37 minutes (Waters Acquity UPLC BEH C (product number: 186002349)) 18 (Determined by reversed-phase ULC using a column (30 × 2.1 mm, particle size 1.7 μm) and a double gradient run of mobile phase B from 1 to 99% over 1.0 min). Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = acetonitrile (0.035% CF3CO2H). Flow rate = 1.5 mL / min, injection volume = 1.5 μL, column temperature = 60°C.

[0325] Preparation of intermediate 4:3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] Step 1: 3-(benzhydrideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate methyl carboxylate [ka] A mixture of methyl 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (47.3 g, 197.43 mmol), diphenylmethaneimine (47 g, 259.33 mmol), xanthophos (9.07 g, 15.675 mmol), and cesium carbonate (131 g, 402.06 mmol) in dioxane (800 mL) was degassed by nitrogen aeration for 30 minutes. Pd(OAc)2 (3.52 g, 15.679 mmol) was added, and the system was purged with nitrogen three times. The reaction mixture was heated at 100 °C for 18 hours. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The cake was washed with phenylethylamine, and the solvent was evaporated under reduced pressure to obtain methyl 3-(benzhydrideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (90 g, 84%) as a yellow solid. ESI-MS m / z calculated value: 384.10855, measured value: 385.1 (M+1) + ;Retention time: 2.24 minutes. LCMS method: Kinetex C 18 4.6 × 50 mm, 2.6 μM, 2.0 mL / min, gradient from 95% H2O (0.1% formic acid) + 5% acetonitrile (0.1% formic acid) to 95% acetonitrile (0.1% formic acid) (2.0 min), followed by holding in 95% acetonitrile (0.1% formic acid) for 1.0 min.

[0326] Step 2: 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] To a methanol (200 mL) suspension of methyl 3-(benzhydrideneamino)-5-(trifluoromethyl)pyridine-2-carboxylate (65 g, 124.30 mmol), HCl (3 M methanol) (146 mL, 3 M, 438.00 mmol) was added. The mixture was stirred at room temperature for 1.5 hours, and then the solvent was removed under reduced pressure. The residue was incorporated into ethyl acetate (2 L) and dichloromethane (500 mL). The organic phase was washed with 5% sodium bicarbonate aqueous solution (3 × 500 mL) and brine (2 × 500 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was pulverized with heptane (2 × 50 mL), and the mother liquor was discarded. The obtained solid was pulverized with a mixture of dichloromethane and heptane (1:1, 40 mL), filtered, and obtained methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (25.25 g, 91%) as a yellow solid. 1 H NMR (300MHz, CDCl3) δ 8.24 (s, 1H), 7.28 (s, 1H), 5.98 (br.s, 2H), 4.00 (s, 3H) ppm. 19 F NMR (282 MHz, CDCl3) δ -63.23 (s, 3F) ppm. ESI-MS m / z calculated value 220.046, measured value 221.1 (M+1). + ;Retention time: 1.62 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0327] Step 3: 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate methyl [ka] To a solution of methyl 3-amino-5-(trifluoromethyl)pyridine-2-carboxylate (18.75 g, 80.91 mmol) in acetonitrile (300 mL), N-bromosuccinimide (18.7 g, 105.3 mmol) was added in small amounts at 0°C. The mixture was stirred overnight at 25°C. Ethyl acetate (1000 mL) was added. The organic layer was washed with 10% sodium thiosulfate solution (3 × 200 mL) and then back-extracted with ethyl acetate (2 × 200 mL). The combined organic extract was washed with saturated sodium bicarbonate solution (3 × 200 mL) and brine (200 mL), dried over sodium sulfate, and concentrated under vacuum to obtain methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (25.46 g, 98%). 1 H NMR (300MHz, CDCl3)δ 3.93-4.03(m,3H),6.01(br.s.,2H),7.37(s,1H)ppm. 19 F NMR (282 MHz, CDCl3): ppm -64.2 (s, 3F). ESI-MS m / z: Calculated value 297.9565, measured value 299.0 (M+1). + ;Holding time: 2.55 minutes. LCMS method: Kinetex C 18 4.6 × 50 mm, 2.6 μM. Temperature: 45°C, Flow rate: 2.0 mL / min, Runtime: 6 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) - 95% acetonitrile (0.1% formic acid) linear gradient over 4.0 min, followed by holding in 95% acetonitrile (0.1% formic acid) for 2.0 min.

[0328] Step 4: 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate methyl carboxylate] [ka] A mixture of methyl 3-amino-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (5 g, 15.549 mmol), (Boc)2O (11 g, 11.579 mL, 50.402 mmol), DMAP (310 mg, 2.5375 mmol), and CH2Cl2 (150 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (0-15% ethyl acetate / heptane) to obtain methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (6.73 g, 87%) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) δ 1.42 (s, 18H), 3.96 (s, 3H), 7.85 (s, 1H) ppm. 19 F NMR (282MHz, CDCl3)δ-63.9(s,3F)ppm. ESI-MS m / z calculated value 498.06134, retention time: 2.34 minutes.LCMS method: Kinetex C 18 4.6 × 50 mm, 2.6 μM. Temperature: 45°C, Flow rate: 2.0 mL / min, Runtime: 3 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) - 95% acetonitrile (0.1% formic acid) linear gradient over 2.0 min, followed by a 1.0 min hold with 95% acetonitrile (0.1% formic acid).

[0329] Preparation of intermediate 5:6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] Step 1: 6-Bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid [ka] A mixture of methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-5-(trifluoromethyl)pyridine-2-carboxylate (247 g, 494.7 mmol) with THF (1.0 L) was mixed with a solution of LiOH (47.2 g, 1.971 mol) in water (500 mL). The mixture was stirred at ambient temperature for 18 hours to obtain a yellow slurry. The mixture was cooled in an ice bath and slowly acidified with HCl (1000 mL 2 M, 2.000 mol) while maintaining the reaction temperature below 15°C. The mixture was diluted with heptane (1.5 L), mixed, and the organic phase was separated. The aqueous phase was extracted with heptane (500 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. Crude oil was dissolved in heptane (600 mL), seeded, and stirred at ambient temperature for 18 hours to obtain a thick slurry. The slurry was diluted with cold heptane (500 mL), and the precipitate was collected using medium-grained frit. The filtered cake was washed with cold heptane, air-dried for 1 hour, and then dried in vacuum at 45°C for 48 hours to obtain 6-bromo-3-(tert-butoxycarbonylamino)-5-(trifluoromethyl)pyridine-2-carboxylic acid (158.3 g, 83%). 1 H NMR (400MHz, DMSO-d6) δ 10.38 (s, 1H), 9.01 (s, 1H), 1.50 (s, 9H) ppm. ESI-MS m / z calculated value 383.99326, measured value 384.9(M+1) + Retention time: 2.55 minutes. LCMS method details: Final purity is measured using Waters Acquity UPLC BEH C (product number: 186002350). 18 The results were determined by reversed-phase ULC using a column (50 × 2.1 mm, particle size 1.7 μm) and a double gradient run of 1-99% mobile phase B over 4.5 minutes. Mobile phase A = H2O (0.05% CF3CO2H). Mobile phase B = acetonitrile (0.035% CF3CO2H). Flow rate = 1.2 mL / min, injection volume = 1.5 μL, column temperature = 60°C.

[0330] Preparation of intermediate 6:3-amino-6-bromo-5-fluoropyridine-2-carboxylate methyl [ka] Step 1: 3-amino-5-fluoropyridine-2-carboxylate methyl carboxylate [ka] 2-bromo-5-fluoropyridine-3-amine (22 g, 115.18 mmol), methanol (250 mL), triethylamine (23.232 g, 32 mL, 229.59 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.1 g, 2.8700 mmol) were added to an autoclave (600 mL). The autoclave was purged with nitrogen, and then with carbon monoxide. The mixture was heated to 130°C and the carbon monoxide pressure was adjusted to 120 psi. The mixture was stirred at 130°C for 3 hours, and then cooled to 25°C. The mixture was purged with nitrogen and concentrated under vacuum. The resulting solid was diluted with ethyl acetate (500 mL). Water (200 mL) and sodium carbonate (15 g) were added, and the mixture was vigorously stirred for 20 minutes. The layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain methyl 3-amino-5-fluoropyridine-2-carboxylate (14.4 g, 53%) as a brown solid. 1 H NMR (400MHz, CDCl3) δ 7.90(s,1H),6.72(d,J=9.8Hz,1H),5.94(br.s,2H),3.96(s,3H)ppm. ESI-MS m / z calculated value 170.04915, measured value 171.1(M+1) + ;Holding time: 1.35 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0331] Step 2: 3-amino-6-bromo-5-fluoropyridine-2-carboxylate methyl carboxylate [ka] To a solution of methyl 3-amino-5-fluoropyridine-2-carboxylate (2.03 g, 11.931 mmol) in acetonitrile (40 mL), N-bromosuccinimide (2.34 g, 13.147 mmol) was added in small amounts. After stirring at room temperature for 2 hours, the reaction mixture was diluted with toluene (150 mL), washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), then dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (20%-60% ethyl acetate / heptane) yielded methyl 3-amino-6-bromo-5-fluoropyridine-2-carboxylate (2.9 g, 98%) as a white solid. 1 H NMR (300MHz, CDCl3) δ 6.80(d,J=8.5Hz,1H),5.98(br.s.,2H),4.22-3.72(m,3H)ppm. 19 F NMR(282MHz, CDCl3)δ-105.70(d,J=9.2Hz,1F)ppm. ESI-MS m / z calculated value 247.9597, measured value 248.9(M+1) + ;Retention time: 1.73 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 3 minutes, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0332] Preparation of intermediate 7: 2-benzyloxy-2-(trifluoromethyl)hexa-5-enhydrazide (hydrochloride) [ka] Step 1: Ethyl 2-hydroxy-2-(trifluoromethyl)hexa-5-enoate [ka] To a solution of ethyl 3,3,3-trifluoro-2-oxopropanoate (25.15 g, 147.87 mmol) in Et2O (270 mL), a solution of bromo(but-3-enyl)magnesium in THF (190 mL, 0.817 M, 155.23 mmol) was added dropwise over 1.5 hours at -78°C (internal temperature -72°C to -76°C). The mixture was stirred at -78°C for 20 minutes. The dry ice-acetone bath was removed. The mixture was slowly warmed to 5°C over 1 hour and added to a mixture of 1N HCl aqueous solution (170 mL) and crushed ice (150 g) (pH=4). The two layers were separated. The organic layer was concentrated, the residue was combined with the aqueous phase, and extracted with siRNA (2 × 150 mL). The combined organic phases were washed with 50 mL of 5% NaHCO3 aqueous solution and brine (20 mL), and dried over Na2SO4. The mixture was filtered, concentrated, and co-evaporated with THF (2 × 40 mL) to obtain ethyl 2-hydroxy-2-(trifluoromethyl)hexa-5-enoate (37.44 g, 96%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ 5.77(ddt,J=17.0,10.4,6.4Hz,1H),5.15-4.93(m,2H),4.49-4.28(m,2H),3 .88(s,1H),2.35-2.19(m,1H),2.17-1.89(m,3H),1.34(t,J=7.0Hz,3H)ppm. 19 F NMR(282MHz, CDCl3)δ-78.74(s,3F)ppm.

[0333] Step 2: 2-Benzyloxy-2-(trifluoromethyl)hexa-5-enoate ethyl [ka] To a solution of ethyl 2-hydroxy-2-(trifluoromethyl)hexa-5-enoate (24.29 g, purity 87.6%, 94.070 mmol) in DMF (120 mL), NaH (60% in mineral oil, 5.64 g, 141.01 mmol) was added in small amounts at 0°C. The mixture was stirred at 0°C for 10 minutes. Benzyl bromide (24.13 g, 141.08 mmol) and TBAI (8.68 g, 23.500 mmol) were added. The mixture was stirred at room temperature overnight. NH4Cl (3 g, 0.6 equivalents) was added. The mixture was stirred for 10 minutes. Ether (30 mL) was added, followed by the addition of ice water (400 g). The mixture was extracted with CH2Cl2, and the combined organic layer was concentrated. Purification by silica gel chromatography (0-20% CH2Cl2 / heptane) yielded ethyl 2-benzyloxy-2-(trifluoromethyl)hexa-5-enoate (26.05 g, 88%) as a pink oil. 1 H NMR(300MHz,CDCl3)δ 1.34(t,J=7.2Hz,3H),2.00-2.19(m,3H),2.22-2.38(m,1H),4.33(q,J=7.2Hz,2H),4.64(d,J =10.6Hz,1H),4.84(d,J=10.9Hz,1H),4.91-5.11(m,2H),5.62-5.90(m,1H),7.36(s,5H)ppm. 19 F NMR (282 MHz, CDCl3) δ -70.5 (s, 3F) ppm. ESI-MS m / z calculated value 316.12863, measured value 317.1 (M+1). + ;Retention time: 2.47 minutes. LCMS method: Kinetex C 18 4.6 × 50 mm, 2.6 μM. Temperature: 45°C, Flow rate: 2.0 mL / min, Runtime: 3 min. Mobile phase: Initial 95% H2O (0.1% formic acid) and 5% acetonitrile (0.1% formic acid) - 95% acetonitrile (0.1% formic acid) linear gradient over 2.0 min, followed by a 1.0 min hold with 95% acetonitrile (0.1% formic acid).

[0334] Step 3: 2-Benzyloxy-2-(trifluoromethyl)hexa-5-enoic acid [ka] A 60 mL aqueous solution of sodium hydroxide (7.86 g, 196.51 mmol) was added to a 210 mL methanol solution of ethyl 2-benzyloxy-2-(trifluoromethyl)hexa-5-enoic acid (24.86 g, 78.593 mmol). The reaction mixture was heated overnight at 50°C. The reaction mixture was concentrated to remove methanol, diluted with water (150 mL), and the sodium carboxylate salt was washed with heptane (1 × 100 mL). The aqueous solution was acidified to pH=2 with 3N HCl aqueous solution. The carboxylic acid was extracted with dichloromethane (3 × 100 mL) and dried over sodium sulfate. The solution was filtered and concentrated to obtain 2-benzyloxy-2-(trifluoromethyl)hexa-5-enoic acid (22.57 g, 97%) as a pale yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 14.31(br.s.,1H),7.55-7.20(m,5H),5.93-5.70(m,1H),5.17-4.91(m,2H),4.85-4.68(m,1H),4.67-4.55(m,1H),2.32-1.94(m,4H)ppm. 19 F NMR(282MHz,DMSO-d6)δ-70.29(s,3F)ppm. ESI-MS m / z calculated value 288.09732, measured value 287.1 (M-1); retention time: 3.1 minutes. LCMS method: Kinetex Polar C 18 3.0 × 50 mm, 2.6 μm, 6 min, 5-95% acetonitrile / H2O (0.1% formic acid) 1.2 mL / min.

[0335] Step 4: N-[[2-benzyloxy-2-(trifluoromethyl)hexa-5-enoyl]amino]carbamate tert-butyl [ka] To a solution of 2-benzyloxy-2-(trifluoromethyl)hexa-5-enoic acid (21.92 g, purity 92.4%, 70.263 mmol) in DMF (130 mL), HATU (37.2 g, 97.836 mmol) and Et3N (15 g, 148.24 mmol) were added. The mixture was stirred for 10 minutes, and then tert-butyl N-aminocarbamate (12.2 g, 92.312 mmol) was added. The mixture was stirred overnight at 25°C and then stirred at 40°C for 1 hour. The mixture was diluted with ice water (500 g) and extracted with CH2Cl2. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography (0-30% siRNA / heptane) yielded N-[[2-benzyloxy-2-(trifluoromethyl)hexa-5-enoyl]amino]carbamate tert-butyl (26.08 g, 92%) as a white solid. 1 H NMR(300MHz,CDCl3)δ 1.46(s,9H),2.10-2.31(m,3H),2.34-2.51(m,1H),4.60-4.72(m,1H),4.73-4.86(m,1H),4.95-5.19(m, 2H), 5.83(ddt,J=16.7,10.4,6.1Hz,1H),6.28(br.s.,1H),7.30-7.51(m,5H),8.34(d,J=2.6Hz,1H)ppm. 19 F NMR (282MHz, CDCl3)ppm-73.6(s,3F)ppm.

[0336] Step 5: 2-Benzyloxy-2-(trifluoromethyl)hexa-5-enhydrazide [ka] To a solution of N-[[2-benzyloxy-2-(trifluoromethyl)hexa-5-enoyl]amino]carbamate tert-butyl (43.12 g, 107.2 mmol) in CH2Cl2 (200 mL), HCl (100 mL 4 M, 400.0 mmol) was added, and the mixture was stirred at ambient temperature for 7 hours. The solvent was removed under vacuum, the residue was removed twice from heptane, and the resulting solid was dried under vacuum using high vacuum for 20 hours to obtain 2-benzyloxy-2-(trifluoromethyl)hexa-5-enhydrazide (hydrochloride) (35 g, 96%). 1 H NMR(400MHz,chloroform-d)δ 9.92(s,2H),7.41-7.31(m,2H),7.30-7.24(m,2H),...

Claims

1. A compound selected from the compounds of formula I, 【Chemical 623】 During the ceremony, X is -O-, -S-, -SO-, and -SO ２ - Selected from, Each Y is independent, -C(R Ｙ ) ２ -, -O-, -CO-, and 【Chemical Formula 624】 Selected from, R Ｙ each independently is hydrogen, halogen, C １ -C ６ -alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxy and Q), C ３ -C ８ -cycloalkyl, C ６ -C １０ -aryl, 5- to 10-membered heteroaryl, -OR Ｙ１ ,-CO ２ R Ｙ１ ,-COR Ｙ１ ,-CON(R Ｙ１ ) ２ , and -NR Ｙ１ - are selected from, or two instances of R Ｙ on the same atom combine to form a ring selected from C ３ -C ８ -cycloalkyl and 3- to 6-membered heterocyclyl, or two instances of R Ｙ where one is on one atom and the other is on an adjacent atom combine to form a π bond, R Ｙ１ Each of them independently consists of hydrogen and C １ -C ６ Selected from alkyl groups, or R groups bonded to the same nitrogen. Ｙ１ These two cases combine to form a 3-6 member heterocycline. Ring B is ■C ６ -C １０ Aryl(halogen, C) １ -C ６ Alkyl and C １ -C ６ (Optionally substituted with 1 to 3 groups independently selected from the alkoxy) ■C ３ -C ８ Cycloalkyl, ■ 5-10 member heteroaryls, and ■ 3-6 member heterocycline (C) １ -C ６ (Optionally substituted with 1 to 3 groups independently selected from alkyl groups) Each Q is independent, ■C １ -C ６ Alkyl, 〇Halogen, Oxo, 〇C ６ -C １０ Aryl(halogen and -OCF) ３ (Optionally substituted by 1 to 3 elements independently selected from, and 〇C ３ -C ８ C is optionally substituted with 1 to 3 groups independently selected from the cycloalkyl group. １ -C ６ Alkyl, ■C ３ -C ８ Cycloalkyl, 〇Halogen, CN, 〇C １ -C ６ Alkyl (halogen, -NH ２ , and (arbitrarily substituted with 1 to 3 elements independently selected from NHCOMe), 〇C １ -C ６ Alkoxy, 〇C ６ -C １０ Ariel (C １ -C ６ (Optionally substituted with 1 to 3 groups independently selected from the alkyl group), and 〇C ３ -C ８ C is optionally substituted with 1 to 3 groups independently selected from the cycloalkyl group. ３ -C ８ Cycloalkyl, ■C ６ -C １０ It is Ariel, 〇Halogen, CN, 〇C １ -C ６ Alkyl (optionally substituted with 1 to 3 groups independently selected from halogens and hydroxyls), 〇C １ -C ６ It is an alkoxy, ■Halogen, ■C ３ -C ８ Cycloalkyl (CF ３ (which is optionally substituted by) C is optionally substituted by 1 to 4 bases independently selected. １ -C ６ Alkoxy, 〇C ３ -C ８ Cycloalkyl (halogen, CF ３ OCF ３ , and C １ -C ６ (Optionally substituted with 1 to 3 groups independently selected from the alkyl group), and 〇C ６ -C １０ C is optionally substituted with 1 to 3 groups independently selected from the aryl group. ６ -C １０ Ariel, ■A 5- to 10-membered heteroaryl, 〇Halogen, 〇C １ -C ６ Alkyl (optionally substituted with 1 to 3 groups independently selected from halogens), 〇C ３ -C ８ Cycloalkyl (1-3 CF ３ (which is optionally substituted in the base), and ○ 5-10 membered heteroaryls, which are arbitrarily substituted with 1-3 groups independently selected from 3-10 membered heterocyclines. ■3- to 10-membered heterocyclines, 〇C １ -C ６ Alkyl (oxo and C ３ -C ８ (Optionally substituted with 1 to 3 groups independently selected from the cycloalkyl group), and Selected from 3-10 membered heterocyclines, which are arbitrarily substituted with 1-3 groups independently selected from the oxo, R １ each independently represents halogen, C １ -C ６ -alkyl optionally substituted with 1 to 6 groups independently selected from halogen and hydroxy, -OR ２ , -N(R ２ ), -CO ２ R ２ , -CO-N(R ２ ), -CN, phenyl, benzyl, C ２ , -C ２ -alkoxy, C １ -C ６ -cycloalkyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, -SO ３ R ８ , -SR ２ , -SOR ２ , -PO(OR ２ ), and -PO(R ２ ), and is selected from ２ , and -PO(R ２ ), and -PO(R ２ ), and is selected from ２ ​ R ２ Each of them independently produces hydrogen and C １ -C ６ Alkyl (optionally substituted with 1 to 6 groups independently selected from halogens), and C ６ -C １０ Aryl (C is optionally substituted with 1 to 6 groups independently selected from halogens) １ -C ６ Selected from (which are optionally substituted with alkoxy), Z is 【Chemical 625】 Selected from, in the formula, ring C is C ６ -C １０ Selected from aryls and 5- to 10-membered heteroaryls, R Ｚ１ However, hydrogen, -CN, C １ -C ６ Selected from alkyl (optionally substituted with 1 to 6 groups independently selected from halogens or 1 to 3 hydroxyls), 3 to 6-membered heterocyclyl, 3 to 6-membered cycloalkyl, 5 to 6-membered aryl, and 5 to 6-membered heteroaryl, R Ｚ２ However, it is selected from hydrogen, halogen, and hydroxyl, or R Ｚ１ and R Ｚ２ Together, they form a group selected from oxo and =N-OH, R Ｚ３ Each of them independently forms hydroxy, C １ -C ６ Alkoxy, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl and C ６ -C １０ Selected from the aryl group, or R Ｚ３ These two cases combine to form a 3-6 member heterocycline. n is selected from 4, 5, 6, 7, and 8. Compounds in which m is selected from 0, 1, 2, and 3, as well as their deuterated derivatives and pharmaceutically acceptable salts.

2. A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein X is -O-.

3. R Ｙ Each of them independently produces hydrogen, halogen, and C. １ -C ６ Alkyl (optionally substituted with 1 to 3 groups independently selected from hydroxyl and Q), C ３ -C ８ Cycloalkyl and -OR Ｙ１ A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

4. R Ｙ Each of them operates independently, Hydrogen, fluorine, 【Chemical 627】 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

5. A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein n is selected from 4, 5, and 6.

6. - (Y) ｎ -but, 【Chemical 629】 【Chemical 630】 A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, which is a group selected from the above.

7. R １ Each of them operates independently, C １ -C ６ Alkyl (optionally substituted with 1 to 6 groups independently selected from halogens and hydroxyls), -N (R ２ ) ２ , and -CO ２ R ２ A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

8. R ２ Each of them independently consists of hydrogen and C １ -C ６ A compound, deuterated derivative, or pharmaceutically acceptable salt selected from alkyl groups according to claim 1.

9. R １ Each of them operates independently, -CF ３ , -NH ２ ,-NH(CH ２ CH ３ ), CO ２ H and CH ２ A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from OH.

10. Z is 【Chemical 631】 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

11. R Ｚ１ However, hydrogen and C １ -C ６ A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, selected from alkyl groups (optionally substituted with one to three groups selected from halogens).

12. R Ｚ１ However, hydrogen and -CF ３ A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

13. R Ｚ２ The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein the compound is hydroxyl.

14. Z is 【Chemical 636】 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

15. A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein m is selected from 1 and 2.

16. X is -O-, Each Y is independent, -C(R Ｙ ) ２ -, -O-, and 【Chemical 637】 Selected from, R Ｙ Each of them independently consists of hydrogen and C １ -C ６ Selected from alkyl groups (optionally substituted with 1 to 3 groups independently selected from hydroxyl and Q), Ring B is C ３ -C ８ Selected from cycloalkyl groups, Q is independent of halogen and C １ -C ６ C is optionally substituted with 1 to 3 groups independently selected from the alkyl group. ３ -C ８ Cycloalkyl and C ６ -C １０ Selected from the alphabet, R １ Each of them operates independently, C １ -C ６ Alkyl (optionally substituted with 1 to 6 groups independently selected from halogens) and -NH ２ Selected from, Z is 【Chemical Formula 638】 And, R Ｚ１ However, C １ -C ６ Selected from alkyl groups (which are optionally substituted with 1 to 6 groups independently of halogens), R Ｚ２ However, it is hydroxyl, n is selected from 5 and 6. The compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein m is 2.

17. R Ｙ Each of them operates independently, hydrogen, 【Chemical 640】 A compound, deuterated derivative, or pharmaceutically acceptable salt selected from the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

18. - (Y) ｎ -but, 【Chemistry 642】 A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, which is a group selected from the above.

19. R Ｚ１ ga-CF ３ The compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 1.

20. A compound, deuterated derivative, or pharmaceutically acceptable salt according to claim 1, wherein n is 6.

21. below: 【Chemical Formula 655】 【Chemical Formula 656】 【Chemical 657】 【Chemical Formula 658】 【Chemistry 659】 【Chemical 660】 【Chemical 661】 【Chemical 662】 【Chemical 663】 【Chemical 664】 【Chemical 665】 【Chemical Formula 666】 【Chemical Formula 667】 【Chemical 668】 Compounds selected from the above, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the above.

22. below: 【Chemical 669】 【Transformation 670】 【Chemistry 671】 【Transformation 672】 【Chemistry 673】 【Transformation 674】 Compounds selected from the above, pharmaceutically acceptable salts thereof, and deuterated derivatives of any of the above.

23. The aforementioned compound, Table 20-1 Table 20-2 The compound according to claim 21, selected from the pharmaceutically acceptable salts thereof and any of the deuterated derivatives described above.

24. The aforementioned compound, Table 21 The compound according to claim 22, selected from the pharmaceutically acceptable salts thereof and any of the deuterated derivatives described above.

25. A pharmaceutical composition comprising a compound, deuterated derivative, or pharmaceutically acceptable salt according to any one of claims 1 to 24, and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition further comprises at least one CFTR corrector.

27. The at least one CFTR corrector is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide (compound II): 【Chemistry 643】 , 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid (compound IV): 【Chemical Formula 644】 N-(1,3-dimethylpyrazole-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound V): 【Chemical 645】 N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound VI): 【Chemical Formula 646】 (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole-1-yl]-12,12-dimethyl-2λ ６ -Tia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII): 【Transformation 647】 (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2,3]hexane-5-yl}-9-oxa-2λ ６ -Tia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (compound VIII): 【Chemical 648】 , PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801 A pharmaceutical composition according to claim 26, selected from the above.

28. A pharmaceutical composition comprising a compound, a deuterated derivative, or a pharmaceutically acceptable salt according to any one of claims 1 to 24, for use in the treatment of cystic fibrosis in patients requiring treatment for cystic fibrosis.

29. The pharmaceutical composition according to claim 28, wherein the pharmaceutical composition further comprises at least one CFTR corrector.

30. The at least one CFTR corrector is (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropane-2-yl)-1H-indole-5-yl)cyclopropanecarboxamide (compound II): 【Chemical Formula 649】 , 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide)-3-methylpyridine-2-yl)benzoic acid (compound IV): 【Chemical 650】 N-(1,3-dimethylpyrazole-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound V): 【Chemical 651】 N-(benzenesulfonyl)-6-[3-[2-[1-(trifluoromethyl)cyclopropyl]ethoxy]pyrazole-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidine-1-yl]pyridine-3-carboxamide (compound VI): 【Chemical 652】 (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazole-1-yl]-12,12-dimethyl-2λ ６ -Tia-3,9,11,18,23-pentazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (compound VII): 【Chemical 653】 (11R)-6-(2,6-dimethylphenyl)-11-(2-methylpropyl)-12-{spiro[2,3]hexane-5-yl}-9-oxa-2λ ６ -Tia-3,5,12,19-tetraazatricyclo[12.3.1.14,8]nonadeca-1(17),4(19),5,7,14(18),15-hexaene-2,2,13-trione (compound VIII) 【Chemical 654】 The pharmaceutical composition according to claim 29, selected from PTI-428, ABBV-2222, ABBV-2851, GLPG2737, ABBV-3221, ABBV-3748, ABBV-3903, ABBV-119, and PTI-801.

31. Substantially crystalline compound 11: 【Chemical 677】 A heptane solvate of a substantially crystalline compound 11, wherein the substantially crystalline nature includes less than 15% amorphous form.

32. formula: 【Chemistry 675】 A compound thereof, a deuterated derivative thereof, or a pharmaceutically acceptable salt of any of the foregoing.

33. formula: 【Chemical Formula 676】 A compound of [this].

34. A pharmaceutical composition comprising the compound, deuterated derivative, or pharmaceutically acceptable salt described in claim 32, or the compound described in claim 33, and a pharmaceutically acceptable carrier.

35. The pharmaceutical composition according to claim 34, further comprising one or more additional therapeutic agents.

36. A pharmaceutical composition comprising the compound according to claim 32, a deuterated derivative, or a pharmaceutically acceptable salt of the compound according to claim 33, for use in the treatment of cystic fibrosis in patients requiring treatment for cystic fibrosis.

37. The pharmaceutical composition according to claim 36, further comprising one or more additional therapeutic agents.

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