Methods and materials for shortening QT prolongation or restoring normal QT intervals

Abstract

This document provides methods and materials for shortening QT prolongation, restoring normal QT intervals, and / or slowing progression of QT prolongation. For example, methods and materials for using soluble guanylate cyclase (sGC) agonists of Group I to shorten QT prolongation, to restore normal QT intervals, and / or so slow progression of QT prolongation are provided. sGC agonists of Group I and compositions containing sGC agonists of Group I also are provided.

Description

[0001] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0002] METHODS AND MATERIALS FOR SHORTENING QT PROLONGATION OR RESTORING NORMAL QT INTERVALS

[0003] TECHNICAL FIELD

[0004] This document relates to methods and materials involved in shortening QT prolongation or restoring normal QT intervals. For example, this document provides methods and materials for using soluble guanylate cyclase (sGC) agonists of Group I (e.g., oxidized or non-oxidized sGC agonists of Group I) to shorten QT prolongation or restore normal QT intervals within a mammal (e.g., a human).

[0005] BACKGROUND A QT interval is calculated from the start of the Q wave to the end of the T wave. Patients with an abnormally long QT interval have an increased risk of developing abnormal heart rhythms and of undergoing sudden cardiac death.

[0006] Clinical data shows that “acquired” QT prolongation (i.e., prolongation of the QT interval in the absence of a clear genetic root cause) occurs in patients with heart diseases. Notably, acquired QT prolongation has been documented in patients with aortic valve stenosis, essential hypertension, heart failure, and a variety of other acquired conditions, and prolongation of the QT interval is predictive of survival in each of these relatively disparate patient populations.

[0007] SUMMARY

[0008] This document provides methods and materials for shortening QT prolongation or restoring normal QT intervals within a mammal (e.g., a human). For example, this document provides soluble guanylate cyclase (sGC) agonists of Group I, compositions containing one or more sGC agonists of Group I, and methods for using sGC agonists of Group I and / or compositions containing one or more sGC agonists of Group I to shorten QT prolongation or restore normal QT intervals within a mammal (e.g., a human).

[0009] As demonstrated herein, administering sGC agonists of Group I to a mammal can be used to shorten QT prolongation or restore normal QT intervals within a mammal (e.g., a human). Having the ability to shorten QT prolongation or restore normal QTAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0010] intervals as described herein can allow patients and clinicians to treat patients who suffer from QT prolongation or are suspected to suffer from QT prolongation.

[0011] In general, one aspect of this document features a method for shortening QT prolongation, restoring normal QT intervals, or slowing progression of QT prolongation. The method can include (or consist essentially of, or consist of) administering a composition containing one or more sGC agonists of Group I to a mammal having QT prolongation, wherein QT prolongation is shortened within the mammal, normal QT intervals are restored within the mammal, or progression of QT prolongation is slowed within the mammal. The mammal can be a human. The method can be for shortening QT prolongation, and wherein QT prolongation is shortened within the mammal. The method can be for restoring normal QT intervals, and wherein normal QT intervals are restored within the mammal. The method can be for slowing progression of QT prolongation, and wherein progression of QT prolongation is slowed within the mammal. The method can include identifying the mammal as having QT prolongation prior to the administering step. At least one of the one or more sGC agonists of Group I can be S3448, YC-I, BAY 58-2667, BAY 41-2272, BAY-41-8543, BAY 63-2521, CFM-1571, A-350619, vericiguat, praliciguat, olinciguat, runcaciguat, bis-heteroaryl pyrazole IWP-051, IW-6463, GSK2181236A, IWP-550, IWP-854, IWP-953, nelociguat, MGV354, BI 703704, S3448, BAY 60-2770, or a pharmaceutically acceptable salt thereof. At least one of the one or more sGC agonists can be a compound of Formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein:

[0014] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0015] X1is selected from -NHS(=O)2- and -S(=O)2NH-;

[0016] X2is selected from -C(=O)NH- and -NHC(=O)-;Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0017] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;

[0018] n is 1, 2, or 3; and

[0019] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula I. R1can be selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be morpholinyl, optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. The compound of Formula (I) can have formula:

[0020]

[0021] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

[0022]

[0023] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0024]

[0025] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

[0026]

[0027] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

[0028]

[0029] or a pharmaceutically acceptable salt thereof. R2can be selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. R2can be selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo. R2can be thiophenyl, optionally substituted with halo. R2can be phenyl, optionally substituted with 1 or 2Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0030] independently selected halo and C1-3 alkoxy. The compound of Formula (I) can have formula:

[0031]

[0032] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

[0033]

[0034] or a pharmaceutically acceptable salt thereof. N can be 1, and R3can be halo. N can be 2, and: each R3can be halo; one R3can be halo, and the other R3can be C1-3 alkoxy; or each R3can be C1-3 alkoxy. The compound of Formula (I) can have formula:

[0035]

[0036] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can have formula:

[0037]

[0038] or a pharmaceutically acceptable salt thereof. The compound of Formula (I) can be selected from any one of the following compounds:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0039]

[0040] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0041]

[0042] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0043]

[0044] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0045]

[0046] or a pharmaceutically acceptable salt thereof.

[0047] In another aspect, this document features a compound of Formula IlaAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0048]

[0049] or a pharmaceutically acceptable salt thereof, wherein:

[0050] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0051] X1is selected from -NHS(=O)2- and -S(=O)2NH-;

[0052] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;

[0053] n is 1, 2, or 3; and

[0054] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula Ila. R1can be selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. The compound of Formula (Ila) can have formula:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0055]

[0056] or a pharmaceutically acceptable salt thereof. The compound of Formula (Ila) can have formula:

[0057]

[0058] or a pharmaceutically acceptable salt thereof. R2can be selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. R2can be selected from thiophenyl, phenyl, and pyrazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, and C1-3 alkoxy. R2can be selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo. The compound of Formula (Ila) can have formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0059]

[0060] or a pharmaceutically acceptable salt thereof. N can be 1, and R3can be halo. N can be 2, and each R3can be C1-3 alkoxy, one R3can be halo, and the other R3can be C1-3 alkoxy, or each R3can be C1-3 alkoxy. The compound of Formula (Ila) can have formula:

[0061]

[0062] or a pharmaceutically acceptable salt thereof. The compound of Formula (Ila) can be selected from any one of the following compounds:

[0063]

[0064] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0065]

[0066] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0067]

[0068] or a pharmaceutically acceptable salt thereof.

[0069] In another aspect, this document features a compound of Formula (lib):Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0070]

[0071] or a pharmaceutically acceptable salt thereof, wherein:

[0072] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0073] X1is selected from -NHC(=O) - and -C(=O) NH-;

[0074] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;

[0075] n is 1, 2, or 3; and

[0076] each R3is independently selected from halo, Ci-3 alkyl, Ci-3 alkoxy, Ci-3 haloalkyl, and Ci-3 haloalkoxy, with the proviso that ataciguat is not included within Formula lib. R1can be selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo. R1can be morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. The compound of Formula (lib) can have formula:

[0077]

[0078] or a pharmaceutically acceptable salt thereof. The compound of Formula (lib) can have formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0079]

[0080] or a pharmaceutically acceptable salt thereof. The compound of Formula (lib) can have formula:

[0081]

[0082] or a pharmaceutically acceptable salt thereof. R2can be selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. R2can be selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo. R2can be pyrazolyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkyl. R2can be pyrimidinyl, optionally substituted with cyclopropyl. N can be 1, and R3can be halo. N can be 2, and: each R3can be C1-3 alkoxy, one R3can be halo, and the other R3can be C1-3 alkoxy, or each R3can be C1-3 alkoxy. The compound of Formula (lib) can have formula:

[0083]

[0084] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0085] or a pharmaceutically acceptable salt thereof. The compound of Formula (lib) can be selected from any one of the following compounds:

[0086]

[0087] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0088]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In another aspect, this document features a compound of formula:

[0091]

[0092] or a pharmaceutically acceptable salt thereof.

[0093] In another aspect, this document features a compound of formula:

[0094]

[0095] or a pharmaceutically acceptable salt thereof.

[0096] In another aspect, this document features a compound of formula:

[0097]

[0098] or a pharmaceutically acceptable salt thereof.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0099] In another aspect, this document features a pharmaceutical composition containing (or consisting essentially of, or consisting of) a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0100] In another aspect, this document features a method for shortening QT prolongation, restoring normal QT intervals, or slowing progression of QT prolongation. The method can include (or consist essentially of, or consist of) administering a composition containing one or more sGC agonists of Group I (e.g., one or more sGC agonists of Group I provided herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a mammal having QT prolongation, wherein QT prolongation is shortened within the mammal, normal QT intervals are restored within the mammal, or progression of QT prolongation is slowed within the mammal. The mammal can be a human. The method can be for shortening QT prolongation, and wherein QT prolongation can be shortened within the mammal. The method can be for restoring normal QT intervals, and wherein normal QT intervals can be restored within the mammal. The method can be for slowing progression of QT prolongation, and wherein progression of QT prolongation can be slowed within the mammal. The method can include identifying the mammal as having QT prolongation prior to the administering step.

[0101] In another aspect, this document features a method for slowing progression of QT prolongation. The method can include (or consist essentially of, or consist of) administering a composition containing one or more sGC agonists of Group I (e.g., one or more sGC agonists of Group I provided herein) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein, to a mammal likely to develop QT prolongation, wherein progression to QT prolongation is delayed within the mammal. The mammal can be a human. The method can include identifying the mammal as being likely to develop QT prolongation prior to the administering step.

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials areAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0103] described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0104] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0105] DESCRIPTION OF DRAWINGS

[0106] Figure 1 contains mass spectrometry results for TC-AT-01.

[0107] Figure 2 contains mass spectrometry results for TC-AT-02.

[0108] Figure 3 contains mass spectrometry results for TC-AT-03.

[0109] Figure 4 contains mass spectrometry results for TC-AT-04.

[0110] Figure 5 contains mass spectrometry results for TC-AT-05.

[0111] Figure 6 contains mass spectrometry results for TC-AT-06.

[0112] Figure 7 contains mass spectrometry results for TC-AT-07.

[0113] Figure 8 contains mass spectrometry results for TC-AT-08.

[0114] Figure 9 contains mass spectrometry results for TC-AT-09.

[0115] Figure 10 contains mass spectrometry results for TC-AT-12.

[0116] Figure 11 contains mass spectrometry results for TC-AT-13.

[0117] Figure 12 contains mass spectrometry results for TC-AT-14.

[0118] Figure 13 contains mass spectrometry results for TC-AT-M1.

[0119] Figure 14 contains mass spectrometry results for TC-AT-M2.

[0120] Figure 15 contains mass spectrometry results for TC-AT-M3.

[0121] Figure 16 contains exemplary synthesis routes for TC-AT-01, TC-AT-02, TC-AT-03, TC-AT-04, TC-AT-05, TC-AT-06, and TC-AT-07, according to some embodiments.

[0122] Figure 17 contains exemplary synthesis routes for TC-AT-08, TC-AT-09, TC-AT-12, TC-AT-13, and TC-AT-14, according to some embodiments.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0123] Figure 18 contains exemplary synthesis routes for TC-AT-M1, TC-AT-M2, and TC-AT-M3, according to some embodiments.

[0124] Figure 19. Effects of riociguat on action potential duration in cardiomyocytes from iPSCs from a patient with long QT syndrome type 2 compared to DMSO in vitro. In vitro effects of increasing doses of the indicated agent on action potential duration in cardiomyocytes from induced pluripotent stem cells (iPSCs) from a patient with long QT syndrome type 2 were assessed. The action potential duration at 90% repolarization (APD90) was measured using a voltage-sensitive fluorophore (FluoVolt) using confocal microscopy with 6 regions of interest were assessed for 20 seconds (pacing rate = 1 Hz). Agents elicit dose-dependent reductions in the APD90. Treatment with 1 pM riociguat significantly shortened APD90 in iPSC-derived cardiomyocytes. Interestingly, however, treatment with higher doses of riociguat (10 pM) did not shorten APD90 in this model system. Asterisk denotes p < 0.05.

[0125] Figure 20. Effects of additional sGC agonists (runcaciguat, cinaciguat, and two additional sGC agonists) on action potential duration in cardiomyocytes from iPSCs from a patient with long QT syndrome type 2 were compared in vitro. Using the same methods described in Figure 19 (voltage-sensitive fluorophore imaging with confocal microscopy), treatment with varying doses of runcaciguat (10 nM, 100 nM) or cinaciguat (10 nM, 100 nM) resulted in significant shortening of the APD90. TC-AT-04 and TC-AT-07 (both tested at 1 pM) also significantly shortened APD90 in iPSC-derived cardiomyocytes. Asterisk denotes p < 0.05.

[0126] Figure 21. Effects of TC-AT-M2, TC-AT-8, and TC-AT-13 (each tested at 1 pM) or sildenafil (a PDE5 inhibitor, which prevents degradation of endogenous cGMP produced by sGC) on action potential duration in cardiomyocytes from iPSCs from a patient with long QT syndrome type 2 in vitro. Using the same imaging methods described in Figure 19, TC-AT-M2 and TC-AT-13 both significantly reduce APD90 in iPSC-derived cardiomyocytes. At a concentration of 1 pM, TC-AT-8 did not significantly shorten the APD90. Treatment with 100 nM Sildenafil did not shorten APD90 in iPSC-derived cardiomyocytes. Asterisk denotes p < 0.05.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0127] Figure 22. Effect of agent treatment in vitro on action potential duration in isolated iPSC-derived cardiomyocytes having dofetilide-induced QT prolongation.

[0128] Figure 23. Effect of vericiguat treatment in vitro on QT interval in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation. Vericiguat paradoxically prolonged QT interval in iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) prolongation as compared to treatment with DMSO.

[0129] Figure 24. Effect of TC-AT-04 and TC-AT-07 treatment in vitro on QT interval in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation. TC-AT-04 and TC-AT-07 shortened QT interval in iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) prolongation as compared to treatment with DMSO.

[0130] Figure 25. Effect of TC-AT-M3 treatment in vitro on QT interval in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation. TC-AT-M3 shortened QT interval in iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) prolongation as compared to treatment with DMSO.

[0131] Figure 26. Effect of TC-AT-13 treatment at various dosages on QT interval in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation in vitro. TC-AT-13 shortened QT interval in iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) prolongation in a dose-dependent manner as compared to treatment with DMSO.

[0132] DETAILED DESCRIPTION

[0133] This document provides methods and materials for shortening QT prolongation or restoring normal QT intervals within a mammal (e.g., a human). For example, this document provides soluble guanylate cyclase (sGC) agonists of Group I, compositions containing one or more sGC agonists of Group I, and methods for using sGC agonists ofAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0134] Group I and / or compositions containing one or more sGC agonists of Group I to shorten QT prolongation or restore normal QT intervals within a mammal (e.g., a human).

[0135] As described herein, one or more sGC agonists of Group I can be administered to a mammal (e.g., a human) to shorten QT prolongation or restore normal QT intervals within the mammal. For example, one or more sGC agonists of Group I can be administered to a mammal (e.g., a human) having QT prolongation (or likely to develop QT prolongation) to shorten QT prolongation or restore normal QT intervals within the mammal.

[0136] Any type of mammal having or likely to develop QT prolongation can be treated as described herein. Examples of mammals that can have or be likely to develop QT prolongation and can be treated as described herein include, without limitation, humans, non-human primates such as monkeys, dogs, cats, horses, cows, pigs, sheep, rabbits, mice, and rats. In some cases, a human having QT prolongation can be treated as described herein. In some cases, a human likely to develop QT prolongation can be treated as described herein.

[0137] Any appropriate method can be used to identify a mammal (e.g., a human) as being a mammal having QT prolongation. For example, QT interval calculations can be used to identify a mammal (e.g., a human) as being a mammal having QT prolongation. Any appropriate method can be used to identify a mammal (e.g., a human) as being a mammal likely to develop QT prolongation. For example, confirmation of a risk of developing aortic valve stenosis, essential hypertension, and / or heart failure can be used to identify a mammal (e.g., a human) as being a mammal likely to develop QT prolongation.

[0138] In some cases, one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be administered to a mammal having QT prolongation (or likely to develop QT prolongation) to shorten QT prolongation or restore normal QT intervals within the mammal. For example, one or more sGC agonists of Group I can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having or likely to develop QT prolongation) shorten QT prolongation or restore normal QT intervals within the mammal. In some cases, the methods and materials described herein can be effective toAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0139] delay the formation of QT prolongation within a mammal by, for example, at least 6 months (e.g., at least about 7 months, at least about 8 months, at least about 10 months, at least about 1 year, at least about 1.5 years, at least about 2 years, at least about 2.5 years, at least about 3 years, at least about 4 years, or at least about 5 years). In some cases, the return of QT prolongation within a mammal being treated as described herein (e.g., by administration of one or more sGC agonists of Group I) can be delayed for as long as the mammal is administered one or more sGC agonists of Group I.

[0140] In some cases, one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be administered to a mammal having QT prolongation to slow the lengthening of QT intervals within the mammal. For example, one or more sGC agonists of Group I can be administered to a mammal (e.g., a human) in need thereof (e.g., a human having QT prolongation) to slow progression (e.g., to slow further lengthening of QT intervals) of that QT prolongation within the mammal. In some cases, the methods and materials described herein can be effective to slow progression of QT prolongation within a mammal by, for example, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or more percent. In some cases, the progression of an existing QT prolongation within a mammal being treated as described herein (e.g., by administration of one or more sGC agonists of Group I) can be reduced to no observable lengthening of QT intervals for as long as the mammal is administered one or more sGC agonists of Group I.

[0141] Any appropriate sGC agonist of Group I can be administered to a mammal (e.g., a human) having (or likely to develop) QT prolongation to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal as described herein.

[0142] Examples of sGC agonists of Group I that can be administered to a mammal (e.g., a human) to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal as described herein include, without limitation, YC-I (5-[l-(phenylmethyl)-lH-indazol-3-yl]-2-furanmethanol), BAY 58-2667 (4-[((4-carboxybutyl)(2-[(4-phenethylbenzyl)oxy] phenethyl)amino)methyl[benzoic]acid hydrochloride; cinaciguat), BAY 41-2272 (3-(4-amino-5-cyclopropylpyrimidin-2-yl)-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridine), BAY-41-8543 (2-[l-[(2-Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0143] fluorophenyl )methyl]-lH-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)-4, 6-pyrimidinediamine), BAY 63-2521 (methyl (4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)(methyl)carbamate; riociguat), CFM-1571 (3-[3-(dimethylamino)propoxy]-N-(4-methoxyphenyl)-l-(phenylmethyl)-lH-pyrazole-5-carboxamide hydrochloride), A-350619 (3-[2-(4-chlorophenylthio)phenyl]-N-(4-dimethylaminobutyl)acrylamide), vericiguat (BAY 1021189, also referred to as MK-1242; methyl (4,6-diamino-2-(5-fluoro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate), praliciguat (IW-1973, IWP-121; l,l,l,3,3,3-hexafluoro-2-[({5-fluoro-2-[l-(2-fluorobenzyl)-5-(l,2-oxazol-3-yl)-lH-pyrazol-3-yl]pyrimidin-4-yl}amino)methyl]propan-2-ol), olinciguat (IW-1701; (2R)-3,3,3-trifluoro-2-{[(5-fluoro-2-{ l-[(2-fhiorophenyl)methyl]- 5-(l,2-oxazol-3-yl)-lH-pyrazol- 3-yl}pyrimidin-4-yl)amino]methyl}-2-hydroxypropanamide), bis-heteroaiyl pyrazole IWP-051 (5-fluoro-2-( 1 -(2-fluorobenzyl)-5 -(i soxazol-3 -yl)- 1 H-pyrazol-3 -yl)pyrimidin-4(3H)-one), IW -6463 , GSK2181236A (l-(6-{2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-2-pyridinyl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid), IWP-550, IWP-854 (4-(5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidin-4-yl)-l-(3-methyl-3H-diazirin-3-yl)-N-(37-oxo-41-((3aS,4S,6aR)-2-oxohexahydro-lH-thieno[3,4-d]imidazol-4-yl)-3,6,9,12,15,18,21,24,27,30,33-undecaoxa-36-azahentetracontyl)-7,10,13,16-tetraoxa-4-azanonadecan-19-amide), IWP-953, nelociguat (methyl (4,6-diamino-2-(l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate; BAY 60-4552), MGV354 ((S)- 1 -(6-(3 -((4-( 1 -(cyclopropanecarbonyl)piperidin-4-yl)-2-methylphenyl)amino)-2,3-dihydro-lH-inden-4-yl)pyridin-2-yl)-5-methyl-lH-pyrazole-4-carboxylic acid), BI 703704 ((lR,5S,8s)-3-(4-(5-methyl-2-((2-methyl-4-(piperidine-l-carbonyl)benzyl)oxy)phenyl)thiazol-2-yl)-3-azabicyclo[3.2.1]octane-8-carboxylic acid), S3448 (2-[[(4-chlorophenyl)sulfonyl]amino]-4,5-dimethoxy-N-[4-(4-thiomorpholinylsulfonyl)phenyl]benzamide), BAY 60-2770 (4-[[(4-carboxybutyl)[2-[5-fluoro-2-[[4'-(trifluoromethyl)[l,r-biphenyl]-4-yl]methoxy]phenyl]ethyl] amino]methyl]benzoic acid), and Runcaciguat (BAY-1101042) ((3S)-3-(4-chloro-3-[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanamido]phenyl}-3-Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0144] cyclopropylpropanoic acid), with the proviso that ataciguat is not included within Group I. See, Buys et al., Nitric Oxide 78:72-78 (2018); Sandner et al., “Soluble Guanylate Cyclase Stimulators and Activators,” In: Handbook of Experimental Pharmacology. Springer, Berlin, Heidelberg, pp. 1-40 (2018); and Friebe et al., Naunyu-Schmiedeherg’s Arch Pharmacol 390:1177-1188 (2017). Additional examples of sGC agonists that can be administered to a mammal (e.g., a human) to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal as described herein include, without limitation, compounds of Formula I and compounds of Formula II (e.g., Formula (Ila) or Formula (lib)), with the proviso that ataciguat is not included within Group I, Formula I, Formula Ila, or Formula lib.

[0145] A sGC agonist of Group I can be a sGC “stimulator” or a sGC “activator.” sGC stimulators bind to sGC and potentiate nitric oxide- (NO-) mediated cGMP signaling. sGC stimulators can increase sGC activity in the absence of NO, but in the presence of NO, sGC stimulators can act synergistically with the NO to amplify NO signaling (see, e.g., Buys et al., supra). sGC activators bind to the heme pocket of the sGC enzyme, and therefore can activate heme-free sGC, independent of NO (see, e.g., Buys et al., supra). In some cases, a sGC agonist of Group I used as described herein can be an activator of an oxidized or non-oxidized form of sGC.

[0146] In some cases, a sGC agonist of Group I used as described herein can be a stimulator that synergistically increases sGC enzyme activity with NO. Examples of sGC stimulators that can be used as described herein include, without limitation, riociguat (BAY 63-2521), vericiguat (BAY 1021189), praliciguat (IW-1973, IWP-121), olinciguat (IW-1701), nelociguat (BAY 60-4552), IW-6463, A-350619, BAY 41-2272, BAY 41-8543, CFM-1571, GSK2181236 A, IWP-051, IWP-550, IWP-854, IWP-953, and YC-1. In some cases, a sGC agonist of Group I used as described herein can be a sGC activator. Examples of sGC activators that can be used as described herein include, without limitation, cinaciguat (BAY 58-2667), MGV354, BI 703704, S3448, runcaciguat (BAY- 1101042), and BAY 60-2770.

[0147] In some cases, an sGC agonist of Formula I can be administered to a mammal (e.g., a human) to shorten QT prolongation, to restore normal QT intervals, and / or to slowAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0148] progression of QT prolongation within the mammal as described herein. In some cases, an sGC agonist of Formula II can be administered to a mammal (e.g., a human) to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal as described herein.

[0149] In some cases, a mammal (e.g., a human) having (or likely to develop) QT prolongation can be administered or instructed to self-administer one or more (e.g., one, two, three, four, or more) sGC agonists of Group I. For example, a mammal (e.g., a human) having (or likely to develop) QT prolongation can be administered a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation as described herein. In some cases, a mammal (e.g., a human) having (or likely to develop) QT prolongation can be instructed to self-administer a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation as described herein.

[0150] In some cases, when a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I is administered to a mammal (e.g., a human) having or likely to develop QT prolongation, the composition can be designed for oral or parenteral (including, without limitation, subcutaneous, intramuscular, intravenous, intradermal, intra-cerebral, intrathecal, intraabdominal, and intraperitoneal injections) administration to the mammal. Compositions suitable for oral administration include, without limitation, liquids, tablets, capsules, pills, powders, gels, and granules.

[0151] Compositions suitable for parenteral administration include, without limitation, aqueous and non-aqueous sterile injection solutions that can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient. In some cases, a pharmaceutically acceptable composition including one or more sGC agonists of Group I can be administered locally or systemically. For example, a composition containing one or more sGC agonists of Group I can be administered systemically by injection to a mammal (e.g., a human). In some cases, each sGC agonist of Group I to be administered when two or more sGC agonists of Group IAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0152] are to be administered can be administered by the same or different routes. For example, riociguat can be administered orally, and YC-I can be administered by injection.

[0153] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be in the form of a sterile injectable suspension (e g., a sterile injectable aqueous or oleaginous suspension). This suspension may be formulated using, for example, suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Examples of acceptable vehicles and solvents that can be used include, without limitation, saline, mannitol, water, Ringer’s solution, and isotonic sodium chloride solution. In some cases, sterile, fixed oils can be used as a solvent or suspending medium. In some cases, a bland fixed oil can be used such as synthetic mono- or di-glycerides.

[0154] When one or more (e.g., one, two, three, four, or more) sGC agonists of Group I are formulated into a composition (e.g., a pharmaceutically acceptable composition) for administration to a mammal (e.g., a human) having or likely to develop QT prolongation to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation as described herein, the composition can deliver the sGC agonist(s) of Group I in any appropriate manner. In some cases, a composition including one or more sGC agonists of Group I can be an immediate release composition (e.g., an immediate release oral dosage form). In some cases, a composition including one or more sGC agonists of Group I can be a controlled (e.g., delayed and / or sustained) release compositions (e.g., a controlled release oral dosage form). For example, a controlled release composition including one or more sGC agonists of Group I can be designed to release the one or more sGC agonists over 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days.

[0155] When designing a composition (e.g., a pharmaceutically acceptable composition) containing one or more sGC agonists of Group I for administration to a mammal (e.g., a human) having or likely to develop QT prolongation to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation as described herein, the composition (e.g., pharmaceutically acceptable composition) can include anyAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0156] appropriate effective amount of the one or more sGC agonists of Group I. For example, a therapeutically effective amount of one or more sGC agonists of Group I can be formulated together with one or more pharmaceutically acceptable carriers (additives), excipients, and / or diluents. Examples of pharmaceutically acceptable carriers, excipients, and diluents that can be used in a composition described herein include, without limitation, cyclodextrins (e.g., beta-cyclodextrins such as KLEPTOSE®), dimethylsulfoxide (DMSO), sucrose, lactose, starch (e.g., starch glycolate), cellulose, cellulose derivatives (e.g., modified celluloses such as microcrystalline cellulose, and cellulose ethers like hydroxypropyl cellulose (HPC) and cellulose ether hydroxypropyl methylcellulose (HPMC)), xylitol, sorbitol, mannitol, gelatin, polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), crosslinked polyvinylpyrrolidone (crospovidone), carboxymethyl cellulose, polyethylene-polyoxypropylene-block polymers, and crosslinked sodium carboxymethyl cellulose (croscarmellose sodium)), titanium oxide, azo dyes, silica gel, fumed silica, talc, magnesium carbonate, vegetable stearin, magnesium stearate, aluminum stearate, stearic acid, antioxidants (e g., vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium), citric acid, sodium citrate, parabens (e.g., methyl paraben and propyl paraben), petrolatum, dimethyl sulfoxide, mineral oil, serum proteins (e.g., human serum albumin), glycine, sorbic acid, potassium sorbate, water, salts or electrolytes (e.g., saline such as phosphate buffered saline, protamine sulfate, di sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyacrylates, waxes, wool fat, lecithin, and com oil. If required, the solubility and bioavailability of the one or more sGC agonists of Group I in a pharmaceutically acceptable composition can be enhanced using lipid excipients and / or block copolymers of ethylene oxide and propylene oxide. See, e.g., U.S. Patent No. 7,014,866 and U.S. Patent Application Publication Nos. 2006 / 0094744 and 2006 / 0079502.

[0157] In some cases, a composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be designed to be in unit-dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze driedAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0158] (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.

[0159] One or more sGC agonists of Group I (e.g., a composition containing one or more sGC agonists of Group I) can be administered to a mammal in any amount, at any frequency, and for any duration effective to achieve a desired outcome (e.g., to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation).

[0160] An effective amount of a sGC agonist of Group I that can be administered to a mammal as described herein can be any amount that shortens QT prolongation, restores normal QT intervals, and / or slows progression of QT prolongation within the mammal without producing significant toxicity to the mammal. For example, an effective amount of a sGC agonist of Group I such as riociguat can be from about 0.0001 mg of riociguat / kg of body weight to about 8000 mg of riociguat / kg of body weight (e.g., from about 0.0001 mg / kg to about 5000 mg / kg, from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.0001 mg / kg to about 500 mg / kg, from about 0.0001 mg / kg to about 100 mg / kg, from about 0.0001 mg / kg to about 50 mg / kg, from about 0.0001 mg / kg to about 20 mg / kg, from about 0.0001 mg / kg to about 10 mg / kg, from about 0.0001 mg / kg to about 1 mg / kg, from about 0.0001 mg / kg to about 0.1 mg / kg, from about 0.0001 mg / kg to about 0.01 mg / kg, from about 0.0001 mg / kg to about 0.001 mg / kg, from about 0.001 mg / kg to about 8000 mg / kg, from about 0.01 mg / kg to about 8000 mg / kg, from about 0.1 mg / kg to about 8000 mg / kg, from about 1 mg / kg to about 8000 mg / kg, from about 10 mg / kg to about 8000 mg / kg, from about 20 mg / kg to about 8000 mg / kg, from about 50 mg / kg to about 8000 mg / kg, from about 100 mg / kg to about 8000 mg / kg, from about 500 mg / kg to about 8000 mg / kg, from about 1000 mg / kg to about 8000 mg / kg, from about 5000 mg / kg to about 8000 mg / kg, from about 0.001 mg / kg to about 5000 mg / kg, from about 0.01 mg / kg to about 1000 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 50 mg / kg, from about 0.0001 mg / kg to about 0.01 mg / kg, from about 0.001 mg / kg to about 0.1 mg / kg, from about 0.01 mg / kg to about 1 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 20 mg / kg, from about 10 mg / kg to about 50 mg / kg,Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0161] from about 20 mg / kg to about 100 mg / kg, from about 50 mg / kg to about 500 mg / kg, from about 100 mg / kg to about 1000 mg / kg, from about 500 mg / kg to about 5000 mg / kg, or from about 1000 mg / kg to about 8000 mg / kg). In some cases, between about 0.1 mg and 200 mg (e.g., between about 0.1 mg and 150 mg, between about 0.1 mg and 100 mg, between about 0.1 mg and 50 mg, between about 0.1 mg and 20 mg, between about 0.1 mg and 10 mg, between about 0.1 mg and 5 mg, between about 0.1 mg and 1 mg, between about 1 mg and 200 mg, between about 5 mg and 200 mg, between about 10 mg and 200 mg, between about 20 mg and 200 mg, between about 50 mg and 200 mg, between about 100 mg and 200 mg, between about 150 mg and 200 mg, between about 1 mg and 150 mg, between about 5 mg and 100 mg, between about 10 mg and 50 mg, between about 0.1 mg and 5 mg, between about 1 mg and 10 mg, between about 5 mg and 20 mg, between about 10 mg and 50 mg, between about 20 mg and 100 mg, between about 50 mg and 150 mg, or between about 100 mg and 200 mg) of a sGC agonist of Group I such as riociguat can be administered to an average sized human (e.g., about 70 kg human) daily for about 20 weeks. If a particular mammal fails to respond to a particular amount, then the amount of sGC agonist of Group I can be increased by, for example, two-fold. After receiving this higher amount, the mammal can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly. Reciprocally, if a mammal experiences side effects at an initial dose (e.g., blood pressure lowering), the amount of sGC agonist of Group I can be decreased while still monitoring for efficacy with regards to QT prolongation. The effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal’s response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition (e.g., degree of QT prolongation) can require an increase or decrease in the actual effective amount administered.

[0162] A composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be administered to a mammal (e.g., a human) having or likely to develop QT prolongation in any appropriate frequency. The frequency of administrationAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0163] can be any frequency that shortens QT prolongation, restores normal QT intervals, and / or slows progression of QT prolongation within the mammal without producing significant toxicity to the mammal. For example, the frequency of administration can be from about once a week to about three times a day, or from about twice a month to about six times a day, or from about twice a week to about once a day. The frequency of administration can remain constant or can be variable during the duration of treatment. A course of treatment with a composition containing one or more sGC agonists of Group I can include rest periods. For example, a composition containing one or more sGC agonists of Group I can be administered daily over a two week period followed by a two week rest period, and such a regimen can be repeated multiple times. As with the effective amount, various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, route of administration, and severity of the condition (e.g., degree of QT prolongation) can require an increase or decrease in administration frequency.

[0164] A composition containing one or more (e.g., one, two, three, four, or more) sGC agonists of Group I can be administered to a mammal (e.g., a human) having or likely to develop QT prolongation for any appropriate duration. An effective duration for administering a composition containing one or more sGC agonists of Group I can be any duration that shortens QT prolongation, restores normal QT intervals, and / or slows progression of QT prolongation within the mammal without producing significant toxicity to the mammal. In some cases, the effective duration can vary from several days to several weeks, months, or years. In general, the effective duration for the treatment of QT prolongation as described herein can range in duration from several months to several years. In some cases, an effective duration can be for as long as an individual mammal is alive. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the condition (e.g., degree of QT prolongation) being treated.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0165] In some cases, methods for treating a mammal (e.g., a human) having or likely to develop QT prolongation as described herein (e.g., by administering one or more sGC agonists of Group I) can include administering to the mammal the one or more (e.g., one, two, three, four, or more) sGC agonists of Group I as the sole active ingredient(s) to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal. For example, a composition containing one or more sGC agonists of Group I can include the one or more sGC agonists of Group I as the sole active ingredient in the composition that is effective to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal.

[0166] In some cases, methods for treating a mammal (e.g., a human) having or likely to develop QT prolongation as described herein (e.g., by administering one or more sGC agonists of Group I) can include administering to the mammal the one or more (e.g., one, two, three, four, or more) sGC agonists of Group I in combination with one or more cGMP-specific phosphodiesterase 5A (PDE5A) inhibitors. In some cases, the one or more sGC agonists of Group I can be administered together as a single composition with the one or more PDE5A inhibitors. In some cases, the one or more sGC agonists of Group I and the one more PDE5A inhibitors can be administered to the mammal being treated at the same time as separate compositions. In some cases, the one or more sGC agonists of Group I can be administered to the mammal first followed by the one more PDE5A inhibitors. In some cases, the one more PDE5A inhibitors can be administered to the mammal first followed by the one or more sGC agonists of Group I. Examples of PDE5A inhibitors include, without limitation, sildenafil, vardenafil, tadalafil, EMD 360527, DA 8159, UK-343-664 (Walker et al., Xenobiotica, 31:651-664 (2001)), UK-427-387, UK-357903 ([l-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2 -methoxy ethoxy)-5 -pyridyl sulphonyl (piperazine]) (Gardiner et al., J. Pharmacol. Exp. Ther., 312:265-271 (2005)), UK-371800 (Pfizer), UK-313794 (Pfizer), UK-343664 (Abel et al., Xenobiotica, 31:665-76 (2001)), TA-1790 (Tanabe Seiyaku), CP-248 (Osi Pharmaceuticals), CP -461 (Osi Pharmaceuticals), exisulind (Deguchi et al., Molecular Cancer Therapeutics, 803-809 (2002); (OsiAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0167] Pharmaceuticals)), pyrazolinone, EMD82639 (Merck KgaA, Darmstadt, DE; (4-(4-[2-ethyl-phenylamino)-methylene]-3-methyl-5-oxo-4,5-di-hydro-pyrazol-l-yl)-benzoic acid; Senzaki et al., FASEBJ., 15:1718-1726 (2001), and Scutt et al., BMC Pharmacol., 4:10 (2004)), EMD360527 (Merck KgaA, Darmstadt, DE; [7-(3-Chloro-4-methoxy-benzylamino)-l-methyl-3-propyl-lH-pyrazolo[4,3-d]pyrimidin-5-ylmethoxy]-acetic acid; Scutt et al., BMC Pharmacol., 4:10 (2004)), EMD221829 (Merck KgaA, Darmstadt, DE; 4-[4-(3-Chloro-4-methoxy-benzylamino)-benzo[4,5]thieno[2,3-d]-pyrimidin-2-yl]-cyclohexanecarboxylic acid, ethanolamin salt; Scutt et al., BMC Pharmacol., 4:10 (2004)), EMD171827 (Merck KgaA, Darmstadt, DE; 5-[4-(3-Chloro-4-methoxy-benzylamino)-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidin-2-yl]-pentanoic acid; Scutt et al., BMC Pharmacol., 4:10 (2004)), DA-8259 (3-(l-Methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide), E-4021 (Dukarm et al., Am. J. Respir. Crit. Care Med., 160:858-865 (1999)), pentoxifylline, and FR22934 (Fujisawa). Additional examples of PDE5A inhibitors can be set forth in U.S. Patent Nos: 6,916,927, 6,911,542, 6,903,099, 6,878,711, 6,872,721, 6,858,620, 6,825,197, 6,774,128, 6,723,719, 6,699,870, 6,670,366, 5,859,006, and 5,250,534 and International Patent Application Publication No. WO 03 / 063875, WO 03 / 1012761, WO 2004 / 037183, and WO 98 / 38168.

[0168] In some cases, a course of treatment and the severity of QT prolongation and / or progression can be monitored. Any appropriate method can be used to determine whether or not treatment with one or more sGC agonists of Group I as described herein is effective to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within the mammal being treated. For example, progression of QT prolongation during a course of treatment described herein can be assessed by calculating QT intervals at different time points.

[0169] This document also provides sGC agonists of Group I and compositions containing one or more sGC agonists of Group I. For example, in some cases, a sGC agonist of Group I that can be used to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within a mammal (e.g., a human) can be a compound of Formula I. In some cases, a sGC agonist of Group I thatAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0170] can be used to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within a mammal (e.g., a human) can be a compound of Formula II (e.g., Formula (Ila) or Formula (lib)). In some cases, a sGC agonist of Group I that can be used to shorten QT prolongation, to restore normal QT intervals, and / or to slow progression of QT prolongation within a mammal (e.g., a human) can be TC-AT-Ml, TC-AT-M2, or TC-AT-M3. In some cases, a composition containing one or more sGC agonists of Group I can include one or more PDE5A inhibitors.

[0171] Compounds of Formula (I)

[0172] In some embodiments, this document provides a compound of Formula (I):

[0173]

[0174] or a pharmaceutically acceptable salt thereof, wherein:

[0175] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0176] X1is selected from -NHS(=O)2- and -S(=O)2NH-;

[0177] X2is selected from -C(=O)NH- and -NHC(=O)-;

[0178] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;

[0179] n is 1, 2, or 3; and

[0180] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula I.

[0181] In some embodiments, R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0182] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

[0183] In some embodiments, R1is morpholinyl, optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0184] In some embodiments, R1is morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0185] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo, and morpholinyl substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0186] In some embodiments, R1is morpholinyl. In some embodiments, R1is piperidinyl. In some embodiments, R1is pyrrolidinyl. In some embodiments, R1is piperazinyl. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 C1-3 alkyl. In some embodiments, R1is piperazinyl, optionally substituted with oxo.

[0187] In some embodiments, the compound of Formula (I) has formula:

[0188]

[0189] or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments, X1is -NHS(=O)2-.

[0191] In some embodiments, X1is -S(=O)2NH-.

[0192] In some embodiments, X2is -NHC(=O) -.

[0193] In some embodiments, X2is -C(=O) NH-.

[0194] In some embodiments, the compound of Formula (I) has formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0195]

[0196] or a pharmaceutically acceptable salt thereof.

[0197] In some embodiments, the compound of Formula (I) has formula:

[0198]

[0199] or a pharmaceutically acceptable salt thereof.

[0200] In some embodiments, the compound of Formula (I) has formula:

[0201]

[0202] or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the compound of Formula (I) has formula:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0204]

[0205] or a pharmaceutically acceptable salt thereof.

[0206] In some embodiments, R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

[0207] In some embodiments, R2is selected from thiophenyl, phenyl, and pyrazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0208] In some embodiments, R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.

[0209] In some embodiments, R2is thiophenyl. In some embodiments, R2is phenyl. In some embodiments, R2is pyrazolyl. In some embodiments, R2is pyrimidinyl. In some embodiments, R2is benzyl.

[0210] In some embodiments, R2is thiophenyl, optionally substituted with halo.

[0211] In some embodiments, R2is phenyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkoxy.

[0212] In some embodiments, the compound of Formula (I) has formula:

[0213]

[0214] or a pharmaceutically acceptable salt thereof.

[0215] In some embodiments, the compound of Formula (I) has formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0216]

[0217] or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, n is 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3.

[0219] In some embodiments, R3is selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0220] In some embodiments, R3is selected from halo and C1-3 alkoxy.

[0221] In some embodiments, R3is halo. In some embodiments, R3is C1-3 alkoxy. In some embodiments, n is i and R3is halo. In some embodiments, n is 2 and each R3is halo. In some embodiments, n is 2, one R3is halo, and the other R3is C1-3 alkoxy. In some embodiments, n is 2 and each R3is C1-3 alkoxy.

[0222] In some embodiments, the compound of Formula (I) has formula:

[0223]

[0224] or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the compound of Formula (I) has formula:

[0226]

[0227] or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound of Formula (I) is selected from any one of the following compounds:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0229]

[0230] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0231]

[0232] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0233]

[0234] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0235]

[0236] or a pharmaceutically acceptable salt thereof.

[0237] Compounds of Formula (II)

[0238] In some embodiments, this document provides a compound of Formula (Ila):Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0239]

[0240] or a pharmaceutically acceptable salt thereof, wherein:

[0241] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0242] X1is selected from -NHS(=O)2- and -S(=O)2NH-;

[0243] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;

[0244] n is 1, 2, or 3; and

[0245] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula Ila.

[0246] In some embodiments, R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

[0247] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

[0248] In some embodiments, R1is morpholinyl, optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0249] In some embodiments, R1is morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0250] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, and oxo, and morpholinyl substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0251] In some embodiments, R1is morpholinyl. In some embodiments, R1is piperidinyl. In some embodiments, R1is pyrrolidinyl. In some embodiments, R1is piperazinyl. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 C1-3 alkyl. In some embodiments, R1is piperazinyl, optionally substituted with oxo.

[0252] In some embodiments, the compound of Formula (Ila) has formula:

[0253]

[0254] or a pharmaceutically acceptable salt thereof.

[0255] In some embodiments, X1is -NHS(=O)2-.

[0256] In some embodiments, X1is -S(=O)2NH-.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0257] In some embodiments, the compound of Formula (Ila) has formula:

[0258]

[0259] or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

[0261] In some embodiments, R2is selected from thiophenyl, phenyl, and pyrazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0262] In some embodiments, R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.

[0263] In some embodiments, R2is thiophenyl. In some embodiments, R2is phenyl. In some embodiments, R2is pyrazolyl. In some embodiments, R2is pyrimidinyl. In some embodiments, R2is benzyl.

[0264] In some embodiments, R2is thiophenyl, optionally substituted with halo.

[0265] In some embodiments, R2is phenyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkoxy.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0266] In some embodiments, the compound of Formula (Ila) has formula:

[0267]

[0268] or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, n is 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3.

[0270] In some embodiments, R3is selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0271] In some embodiments, R3is selected from halo and C1-3 alkoxy.

[0272] In some embodiments, R3is halo. In some embodiments, R3is C1-3 alkoxy. In some embodiments, n is 1 and R3is halo. In some embodiments, n is 2 and each R3is halo. In some embodiments, n is 2, one R3is halo, and the other R3is C1-3 alkoxy. In some embodiments, n is 2 and each R3is C1-3 alkoxy.

[0273] In some embodiments, the compound of Formula (Ila) has formula:

[0274]

[0275] or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the compound of Formula (Ila) is selected from any one of the following compounds:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0277]

[0278] Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0279]

[0280] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0281]

[0282] or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, this documents provides a compound of Formula (lib):

[0284]

[0285] or a pharmaceutically acceptable salt thereof, wherein:

[0286] R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;

[0287] X1is selected from -NHC(=O) - and -C(=O) NH-;

[0288] R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, Ci-3 alkoxy, Ci-3 haloalkyl, Ci-3 haloalkoxy, and cyclopropyl;

[0289] n is 1, 2, or 3; and

[0290] each R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula lib .

[0291] In some embodiments, R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0292] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

[0293] In some embodiments, R1is morpholinyl, optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0294] In some embodiments, R1is morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0295] In some embodiments, R1is selected from piperidinyl, pyrrolidinyl, piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo, and morpholinyl substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

[0296] In some embodiments, R1is morpholinyl. In some embodiments, R1is piperidinyl. In some embodiments, R1is pyrrolidinyl. In some embodiments, R1is piperazinyl. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH. In some embodiments, R1is morpholinyl or piperidinyl, each of which is optionally substituted with 1 or 2 C1-3 alkyl. In some embodiments, R1is piperazinyl, optionally substituted with oxo.

[0297] In some embodiments, the compound of Formula (lib) has formula:

[0298]

[0299] or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, X1is -NHC(=O)-.

[0301] In some embodiments, X1is -C(=O) NH-.

[0302] In some embodiments, the compound of Formula (lib) has formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the compound of Formula (lib) has formula:

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

[0309] In some embodiments, R2is selected from thiophenyl, phenyl, and pyrazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0310] In some embodiments, R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.

[0311] In some embodiments, R2is thiophenyl. In some embodiments, R2is phenyl. In some embodiments, R2is pyrazolyl. In some embodiments, R2is pyrimidinyl. In some embodiments, R2is benzyl.

[0312] In some embodiments, R2is thiophenyl, optionally substituted with halo.

[0313] In some embodiments, R2is phenyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkoxy.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0314] In some embodiments, R2is pyrazolyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkyl.

[0315] In some embodiments, R2is pyrimidinyl, optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl. In some embodiments, R2is pyrimidinyl, optionally substituted with cyclopropyl.

[0316] In some embodiments, n is 1. In some embodiments, n is 1 or 2. In some embodiments, n is 2. In some embodiments, n is 2 or 3. In some embodiments, n is 3.

[0317] In some embodiments, R3is selected from halo, C1-3 alkyl, and C1-3 alkoxy.

[0318] In some embodiments, R3is selected from halo and C1-3 alkoxy.

[0319] In some embodiments, R3is halo. In some embodiments, R3is C1-3 alkoxy. In some embodiments, n is i and R3is halo. In some embodiments, n is 2 and each R3is halo. In some embodiments, n is 2, one R3is halo, and the other R3is C1-3 alkoxy. In some embodiments, n is 2 and each R3is C1-3 alkoxy.

[0320] In some embodiments, the compound of Formula (lib) has formula:

[0321]

[0322] or a pharmaceutically acceptable salt thereof.

[0323] In some embodiments, the compound of Formula (lib) is selected from any one of the following compounds:

[0324]

[0325] Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0326]

[0327] or a pharmaceutically acceptable salt thereof.

[0328] In some embodiments, this document provides a compound of formula:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0329]

[0330] or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, this document provides a compound of formula:

[0332]

[0333] or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, this document provides a compound of formula:

[0335]

[0336] or a pharmaceutically acceptable salt thereof.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0337] In some embodiments, this document provides a compound of formula:

[0338]

[0339] or a pharmaceutically acceptable salt thereof.

[0340] In some embodiments, a salt of a compound of Formula I, Formula II, or any other sGC agonist of Group I can be formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group, for use as described herein. In some cases, a sGC agonist of Group I can be a pharmaceutically acceptable acid addition salt of a sGC agonist of Group I.

[0341] In some cases, acids commonly used to form pharmaceutically acceptable salts of a sGC agonist of Group I can include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0342] 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthal ene-1 -sulfonate, naphthalene-2- sulfonate, mandelate and other salts. In some cases, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0343] In some cases, bases commonly used to form pharmaceutically acceptable salts of a sGC agonist of Group I can include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. In some cases, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be substantially isolated.

[0344] A sGC agonist of Formula I, a sGC agonist of Formula II, or any other sGC agonist of Group I, including salts thereof, can be prepared using organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. For example, appropriate synthetic protocols can be selected and implemented to synthesize the sGC agonists of Group I described herein.

[0345] Suitable synthetic methods of starting materials, intermediates and products can be identified by reference to the literature, including reference sources such as: Advances in Heterocyclic Chemistry, Vol. 1-107 (Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vol. 1-49 (J. Heterocyclic ( 'hem., 1964-2012); Carreira et al. (Ed.) Science of Synthesis, Vol. 1-48 (2001-2010) and Knowledge Updates KU2010 / 1-4; 2011 / 1-4;

[0346] 2012 / 1-2 (Thieme, 2001-2012); Katritzky et al. (Ed.) Comprehensive Organic FunctionalAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0347] Group Transformations, (Pergamon Press, 1996); Katritzky et al. (Ed ); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd Edition, 2004); Katritzky et al. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); and Trost et al. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0348] The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

[0349] Preparation of the compounds provided herein can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, Inc., New York (2006).

[0350] Selected definitions

[0351] As used herein, the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

[0352] At various places in this document, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the subject matter include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, Cs alkyl, and Ce alkyl.Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0353] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0354] Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include Ci-4, Ci-6, and the like.

[0355] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moi eties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, / / -butyl, te / 7-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, / / -pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0356] As used herein, the term “Cn-m haloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+l halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0357] As used herein, the term “Cn-m alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., / / -propoxy and isopropoxy), butoxy (e.g., / / -butoxy and / c / 7-butoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0358] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In someAtorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0359] embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0360] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. As used herein, the term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g., C=O), or attached to a heteroatom forming a sulfoxide or sulfone group.

[0361] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0362] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds described herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated. Cis and trans geometric isomers of the compounds provided herein are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the ^-configuration. In some embodiments, the compound has the ^-configuration.

[0363] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0364] pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0365] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

[0366] EXAMPLES

[0367] Example 1 - TC-AT-01

[0368] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-01 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0369] Mass spectrometry confirmed production of this compound (Figure 1).

[0370] Example 2 - TC-AT-02

[0371] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-02 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0372] Mass spectrometry confirmed production of this compound (Figure 2).

[0373] Example 3 - TC-AT-03

[0374] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-03 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0375] Mass spectrometry confirmed production of this compound (Figure 3).

[0376] Example 4 - TC-AT-04

[0377] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-04 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0378] Mass spectrometry confirmed production of this compound (Figure 4).Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0379] Example 5 - TC-AT-05

[0380] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-05 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0381] Mass spectrometry confirmed production of this compound (Figure 5).

[0382] Example 6 - TC-AT-06

[0383] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-06 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0384] Mass spectrometry confirmed production of this compound (Figure 6).

[0385] Example 7 - TC-AT-07

[0386] Synthesis was based on building block chemistry, click chemistry, and fragment based chemistry. TC-AT-07 was synthesized in one step via amide coupling starting from the corresponding acids and anilines (Figure 16).

[0387] Mass spectrometry confirmed production of this compound (Figure 7).

[0388] Example 8 - TC-AT-08

[0389] An approach similar to those of Schemes 8, 9, and 10 was used to synthesis TC-AT-08. An additional step of ester group hydrolysis was performed as well (Figure 17).

[0390] Mass spectrometry confirmed production of this compound (Figure 8).

[0391] Example 9 - TC-AT-09

[0392] An approach similar to those of Schemes 8, 9, and 10 was used to synthesis TC-AT-09. An additional step of ester group hydrolysis was performed as well (Figure 17).

[0393] Mass spectrometry confirmed production of this compound (Figure 9).Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0394] Example 10 - TC- AT- 12

[0395] An approach similar to those of Schemes 8, 9, and 10 was used to synthesis TC-AT-12. An additional step of ester group hydrolysis was performed as well (Figure 17).

[0396] Mass spectrometry confirmed production of this compound (Figure 10).

[0397] Example 11 -TC-AT-13

[0398] An approach similar to those of Schemes 8, 9, and 10 was used to synthesis TC-AT-13. An additional step of ester group hydrolysis was performed as well (Figure 17).

[0399] Mass spectrometry confirmed production of this compound (Figure 11).

[0400] Example 12 - TC-AT-14

[0401] An approach similar to those of Schemes 8, 9, and 10 was used to synthesis TC-AT-14. An additional step of ester group hydrolysis was performed as well (Figure 17).

[0402] Mass spectrometry confirmed production of this compound (Figure 12).

[0403] Example 13 -TC-AT-M1

[0404] TC-AT-M1 was synthesized via a two-step synthetic route. In the first turn, synthesis of the corresponding sulfonamides starting from the sulfonyl chloride and amino acid was carried out followed by further amide coupling (Figure 18).

[0405] Mass spectrometry confirmed production of this compound (Figure 13).

[0406] Example 14-TC-AT-M2

[0407] TC-AT-M2 was synthesized via a two-step synthetic route. In the first turn, synthesis of the corresponding sulfonamides starting from the sulfonyl chloride and amino acid was carried out followed by further amide coupling (Figure 18).

[0408] Mass spectrometry confirmed production of this compound (Figure 14).Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0409] Example 15 -TC-AT-M3

[0410] TC-AT-M3 was synthesized via a two-step synthetic route. In the first turn, synthesis of the corresponding sulfonamides starting from the sulfonyl chloride and amino acid was carried out followed by further amide coupling (Figure 18).

[0411] Mass spectrometry confirmed production of this compound (Figure 15).

[0412] Example 16 - Shortening QT Prolongation

[0413] A human identified as having QT prolongation is administered a composition containing 0.01 mg to 400 mg (e.g., 1 mg to 300 mg, or 10 mg to 250 mg) of an sGC agonist of Group I (e.g., riociguat or other sGC agonist of Group I described herein) daily. After administering the sGC agonist of Group I daily for 30 days, QT prolongation within the human is shortened.

[0414] Example 17 - Restoring Normal QT Intervals

[0415] A human identified as having QT prolongation is administered a composition containing 0.01 mg to 400 mg (e.g., 1 mg to 300 mg, or 10 mg to 250 mg) of an sGC agonist of Group I (e.g., riociguat or other sGC agonist of Group I described herein) daily. After administering the sGC agonist of Group I daily for 10-30 days, QT intervals within the human returned to normal.

[0416] Example 18 - Role of sGC agonists of Group I in long QT The effect of in vitro vericiguat treatment on QT interval was assessed in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation. As compared to treatment with DMSO, vericiguat paradoxically prolonged the QT interval in the iPSC-derived cardiomyocytes having G604S-KCNH2-driven QT prolongation (Figure 23).

[0417] The effects of TC-AT-04 and TC-AT-07 treatment on QT interval in vitro in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation were then assessed. As compared to treatment withAttorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379

[0418] DMSO, both TC-AT-04 and TC-AT-07 shortened the QT interval in the iPSC-derived cardiomyocytes having G604S-KCNH2-driven QT prolongation (Figure 24).

[0419] The effects of TC-AT-M3 and TC-AT-13 on QT interval also were tested in vitro in isolated iPSC-derived cardiomyocytes having long QT syndrome type 2 mutation-driven (G604S-KCNH2) QT prolongation. TC-AT-M3 shortened the QT interval in the iPSC-derived cardiomyocytes having G604S-KCNH2-driven QT prolongation as compared to treatment with DMSO (Figure 25). In addition, TC-AT-13 treatment shortened the QT interval in the iPSC-derived cardiomyocytes having G604S-KCNH2-driven QT prolongation in a dose-dependent manner, as compared to treatment with DMSO (Figure 26). See, also, Figure 22.

[0420] OTHER EMBODIMENTS

[0421] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379WHAT IS CLAIMED IS:

1. A method for shortening QT prolongation, restoring normal QT intervals, or slowing progression of QT prolongation, wherein said method comprises administering a composition comprising one or more sGC agonists to a mammal having QT prolongation, wherein QT prolongation is shortened within said mammal, normal QT intervals are restored within said mammal, or progression of QT prolongation is slowed within said mammal, with the proviso that said one or more sGC agonists does not include ataciguat.

2. The method of claim 1, wherein said mammal is a human.

3. The method of any one of claims 1-2, wherein said method is for shortening QT prolongation, and wherein QT prolongation is shortened within said mammal.

4. The method of any one of claims 1-2, wherein said method is for restoring normal QT intervals, and wherein normal QT intervals are restored within said mammal.

5. The method of any one of claims 1-2, wherein said method is for slowing progression of QT prolongation, and wherein progression of QT prolongation is slowed within said mammal.

6. The method of any one of claims 1-5, wherein said method comprises identifying said mammal as having QT prolongation prior to said administering step.

7. The method of any one of claims 1-6, wherein at least one of said one or more sGC agonists is S3448, YC-I, BAY 58-2667, BAY 41-2272, BAY-41-8543, BAY 63-2521, CFM-1571, A-350619, vericiguat, praliciguat, olinciguat, runcaciguat, bis-heteroaryl pyrazole IWP-051, IW-6463, GSK2181236A, IWP-550, IWP-854, IWP-953, nelociguat, MGV354, BI 703704, S3448, BAY 60-2770, or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-3798. The method of any one of claims 1-7, wherein at least one of said one or more sGC agonists is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;X1is selected from -NHS(=0)2- and -S(=0)2NH-;X2is selected from -C(=O)NH- and -NHC(=O)-;R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;n is 1, 2, or 3; andeach R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula I.

9. The method of claim 8, wherein R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

10. The method of claim 8, wherein R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

11. The method of claim 8, wherein R1is morpholinyl, optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37912. The method of claim 8, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 8-12, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 8-12, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37915. The method of any one of claims 8-12, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 8-12, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 8-16, wherein R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

18. The method of any one of claims 8-16, wherein R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37919. The method of any one of claims 8-16, wherein R2is thiophenyl, optionally substituted with halo.

20. The method of any one of claims 8-16, wherein R2is phenyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkoxy.

21. The method of any one of claims 8-20, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 8-20, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

23. The method of any one of claims 8-22, wherein n is 1 and R3is halo.

24. The method of any one of claims 8-22, wherein n is 2, and:each R3is halo;one R3is halo, and the other R3is C1-3 alkoxy; oreach R3is C1-3 alkoxy.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37925. The method of any one of claims 8-24, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

26. The method of any one of claims 8-24, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

27. The method of claim 8, wherein the compound of Formula (I) is selected from any one of the following compounds:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

28. A compound of Formula Ila:or a pharmaceutically acceptable salt thereof, wherein:R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;X1is selected from -NHS(=0)2- and -S(=0)2NH-;R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 haloalkoxy, and cyclopropyl;Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379n is 1, 2, or 3; andeach R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula Ila.

29. The compound of claim 28, wherein R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

30. The compound of claim 28, wherein R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

31. The compound of claim 28, wherein R1is morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

32. The compound of claim 28, wherein the compound of Formula (Ila) has formula:or a pharmaceutically acceptable salt thereof.

33. The compound of claim 28, wherein the compound of Formula (Ila) has formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 28-33, wherein R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

35. The compound of any one of claims 28-34, wherein R2is selected from thiophenyl, phenyl, and pyrazolyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, and C1-3 alkoxy.

36. The compound of any one of claims 28-34, wherein R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.

37. The compound of any one of claims 28-36, wherein the compound of Formula (Ila) has formula:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 28-37, wherein n is 1 and R3is halo.

39. The compound of any one of claims 28-37, wherein n is 2, andeach R3is C1-3 alkoxy,one R3is halo, and the other R3is C1-3 alkoxy, oreach R3is C1-3 alkoxy.

40. The compound of any one of claims 28-39, wherein the compound of Formula (Ila) has formula:or a pharmaceutically acceptable salt thereof.

41. The compound of claim 28, wherein the compound of Formula (Ila) is selected from any one of the following compounds:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

42. A compound of Formula (lib):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from Ci-3 alkyl, OH, oxo, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy;X1is selected from -NHC(=O) - and -C(=O) NH-;R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, Ci-3 alkyl, Ci-3 alkoxy, Ci-3 haloalkyl, Ci-3 haloalkoxy, and cyclopropyl;n is 1, 2, or 3; andeach R3is independently selected from halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy, with the proviso that ataciguat is not included within Formula lib.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37943. The compound of claim 42, wherein R1is selected from morpholinyl, piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

44. The compound of claim 42, wherein R1is selected from piperidinyl, pyrrolidinyl, and piperazinyl, each of which is optionally substituted with 1 or 2 substituents independently selected from C1-3 alkyl, OH, and oxo.

45. The compound of claim 42, wherein R1is morpholinyl, substituted with 1 or 2 substituents independently selected from C1-3 alkyl and OH.

46. The compound of claim 42, wherein the compound of Formula (lib) has formula:or a pharmaceutically acceptable salt thereof.

47. The compound of claim 42, wherein the compound of Formula (lib) has formula:or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37948. The compound of claim 42, wherein the compound of Formula (Tib) has formula:or a pharmaceutically acceptable salt thereof.

49. The compound of any one of claims 42-48, wherein R2is selected from thiophenyl, phenyl, pyrazolyl, pyrimidinyl, and benzyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo, C1-3 alkyl, C1-3 alkoxy, and cyclopropyl.

50. The compound of any one of claims 42-48, wherein R2is selected from thiophenyl and phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from halo.

51. The compound of any one of claims 42-48, wherein R2is pyrazolyl, optionally substituted with 1 or 2 independently selected halo and C1-3 alkyl.

52. The compound of any one of claims 42-48, wherein R2is pyrimidinyl, optionally substituted with cyclopropyl.

53. The compound of any one of claims 42-52, wherein n is 1 and R3is halo.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37954. The compound of any one of claims 42-52, wherein n is 2, and:each R3is C1-3 alkoxy,one R3is halo, and the other R3is C1-3 alkoxy, oreach R3is C1-3 alkoxy.

55. The compound of any one of claims 42-54, wherein the compound of Formula (lib) has formula:or a pharmaceutically acceptable salt thereof.

56. The compound of claim 42, wherein the compound of Formula (lib) is selected from any one of the following compounds:Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

57. A compound of formula:or a pharmaceutically acceptable salt thereof.

58. A compound of formula:Atorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-379or a pharmaceutically acceptable salt thereof.

59. A compound of formula:or a pharmaceutically acceptable salt thereof60. A pharmaceutical composition comprising a compound of any one of claims 28-59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

61. A method for shortening QT prolongation, restoring normal QT intervals, or slowing progression of QT prolongation, wherein said method comprises administering a composition comprising one or more sGC agonists of any one of claims 28-59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60, to a mammal having QT prolongation, wherein QT prolongation is shortened within said mammal, normal QT intervals are restored within said mammal, or progression of QT prolongation is slowed within said mammal.

62. The method of claim 61, wherein said mammal is a human.Attorney Docket No.: 07039-2395WO1 / 2019-355 / 2023-37963. The method of any one of claims 61-62, wherein said method is for shortening QT prolongation, and wherein QT prolongation is shortened within said mammal.

64. The method of any one of claims 61-62, wherein said method is for restoring normal QT intervals, and wherein normal QT intervals are restored within said mammal.

65. The method of any one of claims 61-62, wherein said method is for slowing progression of QT prolongation, and wherein progression of QT prolongation is slowed within said mammal.

66. The method of any one of claims 61-65, wherein said method comprises identifying said mammal as having QT prolongation prior to said administering step.

67. A method for slowing progression of QT prolongation, wherein said method comprises administering a composition comprising one or more sGC agonists of any one of claims 28-59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60, to a mammal likely to develop QT prolongation, wherein progression to QT prolongation is delayed within said mammal.

68. The method of claim 61, wherein said mammal is a human.

69. The method of any one of claims 67-68, wherein said method comprises identifying said mammal as being likely to develop QT prolongation prior to said administering step.

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